Acyclic Nucleoside Phosphonate Diesters

ABSTRACT

The present disclosure relates, inter alia, to compositions and methods for treating viral diseases and cancer. There are disclosed lipophilic antiviral and anticancer acyclic nucleoside phosphonate diesters, preparation thereof, and methods of using the compounds to treat viral diseases and cancer.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is continuation of U.S. application Ser. No. 16/111,378filed Aug. 24, 2018, which is a continuation of U.S. application Ser.No. 15/809,400 filed Nov. 10, 2017, Issued as U.S. Pat. No. 10,076,533,which is a continuation of U.S. application Ser. No. 15/617,841 filedJun. 8, 2017, issued as U.S. Pat. No. 10,076,532, which is acontinuation of U.S. application Ser. No. 15/179,209 filed Jun. 10,2016, issued as U.S. Pat. No. 9,775,852, which is a continuation of U.S.application Ser. No. 14/874,027 filed Oct. 2, 2015, issued as U.S. Pat.No. 9,387,217, which is a continuation of U.S. application Ser. No.14/463,908 filed Aug. 20, 2014, issued as U.S. Pat. No. 9,156,867, whichis a continuation of U.S. application Ser. No. 14/211,235 filed Mar. 14,2014, issued as U.S. Pat. No. 8,835,630, which claims the benefit ofpriority to U.S. Application No. 61/793,993 filed Mar. 15, 2013, thecontent of each of which is incorporated herein by reference in itsentirety and for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with government support under grant numbersAI071803, AI074057 and EY07366 awarded by the National Institutes ofHealth. The government has certain rights in the invention.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Sep. 6, 2019, isnamed 24978_0517_SL.txt and is 2,042 bytes in size.

BACKGROUND

The present disclosure relates, inter alia, to compositions and methodsfor treating viral diseases and cancer. In one aspect it relates tolipophilic antiviral and anticancer acyclic nucleoside phosphonatediesters, preparation thereof, and methods of using the compounds totreat viral diseases and cancer.

Viruses are infectious particles that can replicate their DNA and RNAonly within host cells. Viral infections may lead to mild or severeillnesses in humans and mammals. Examples of viral infections includehepatitis B and C, smallpox, herpes simplex, cytomegalovirus, humanimmunodeficiency virus (HIV), influenza, adenovirus, chickenpox, BKvirus, JC virus and precancerous lesions caused by infections with thehuman papillomavirus (cervical intraepithelial neoplasia, vaginal andanal intraepithelial neoplasia). Viral infection may also lead to cancerin humans and other species. Viruses known to cause cancer include butare not limited to human papilloma virus (HPV), hepatitis B virus (HBV),hepatitis C virus (HCV), HIV and Epstein Barr virus (EBV). Vaccinationhas been successful in preventing infection from many viruses. Antiviralagents are known that interfere with viral DNA or RNA synthesis andviral replication and are used to prevent or treat viral infections inmammals and humans. For example, combinations of antiviral drugs areused to treat AIDS, hepatitis B, hepatitis C, herpes simplex viruses,cytomegalovirus and influenza. Despite these successes, viral diseasesremain an important public health problem and improved antiviral agentsand anticancer agents are needed. For example, there is presently noapproved antiviral treatment for human papillomavirus infections.

Many antiviral drugs are nucleoside or nucleotide analogs. Examples ofantiviral nucleoside analogs include azidothymidine, acyclovir,ganciclovir, lamivudine and emtricitabine. Acyclic nucleosidephosphonates (ANPs) are a class of nucleotide analogs and are effectiveantiviral agents. Adefovir, tenofovir and cidofovir (CDV) are ANPs thathave been approved for clinical use against human infections with HBV,HIV and CMV, respectively.

ANPs are known in the art not to be absorbed readily from thegastrointestinal tract of mammals because of their molecular weight andthe presence of the double negative charge on the phosphonate. Becauseof their poor oral pharmacokinetic properties, ANPs are usuallyconverted to prodrugs to produce clinically useful therapeutic agents.It has been demonstrated that masking one or both negative charges withpromoieties improves the uptake and transport into the small intestinalenterocytes where the promoiety is cleaved, releasing the ANP into thecirculation; examples include tenofovir disoproxil fumarate and adefovirdipivoxil. Another approach is to prepare alkoxyalkyl or alkylmonoesters of ANPs to increase oral bioavailability of the drug. Withthe alkoxyalkyl ANP monoester approach, side effects may occur whennon-targeted tissues such as the small intestine are overexposed. Forexample, in enterocytes, enzymatic cleavage of the promoiety by aphospholipase C or an acid sphingomyelinase to the ANP may result inlocal toxicity because of further anabolic phosphorylation to the ANPdiphosphate which may inhibit enterocyte DNA synthesis. Lipophilic ANPdiester compounds are anticipated to undergo less cleavage from intactprodrug to ANP in the small intestine enterocytes following oraladministration reducing GI side effects and releasing more drugsubstance into the circulation and producing higher levels of the drugsubstance in the blood.

ANPs or their alkyl or alkoxyalkyl monoesters may exhibit limited uptakein certain target tissues such as the central nervous system. Anadditional advantage of nucleoside phosphonate diesters is the maskingof the remaining negative charge on the phosphonate oxygen with a secondmasking group which can increase penetration of the drug substance intothe central nervous system (CNS) for treatment of CNS viral infections(for example, HIV or JC virus) or for treatment of brain cancers such asglioblastoma. Cancer cells rapidly synthesize DNA and undergouncontrolled cell division. The lipophilic acyclic nucleosidephosphonate (ANP) diester compositions described herein can bemetabolized to their diphosphates which inhibit or block DNA synthesisand cell division in target cancer cells, leading to cell death whilehaving substantially lesser effects on non-malignant cells. Exposure ofvarious types of cancer cells to acyclic nucleoside phosphonatesdiesters may result in much greater cytotoxicity than that observed innormal non-malignant cells. For example, leukemias, lymphomas, brainneoplasms such as glioblastoma and cervical cancer cells may be moresusceptible to the cytotoxic effects when exposed to lipophilic ANPdiesters than the corresponding non-malignant cell lines. Lipophilicacyclic nucleoside phosphonate diesters exhibit more selective toxicity,improved access to the central nervous system and effective topicaluptake for treatment of skin cancers, viral skin infections, cervicalintraepithelial neoplasia (CIN), vaginal and anal intraepithelialdysplasia, venereal warts and related infections caused by the humanpapillomavirus when compared to acyclic nucleoside phosphonate monoestercompositions.

Compounds disclosed herein having both ANP phosphonate negative chargesmasked with functional groups provide for more effective use as topicalagents for treatment of skin cancers and viral infections. Inparticular, compounds disclosed herein provide for efficacious treatmentfor infections of the cervical, vaginal, rectal and penile epitheliumwith the human papilloma virus including the high risk subtypes such as16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 which areassociated with cervical, rectal, penile and vaginal cancer and venerealwarts.

BRIEF SUMMARY

In a first aspect, there is provided a compound with structure ofFormula (I),

or stereoisomer, salt, hydrate, solvate, or crystalline form thereof.Regarding Formula (I), L is a lipophilic promoiety, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl, orO-substituted glyceryl having the formula —CH₂CH(OR¹)—CH₂(OR²) (II),wherein R¹ and R² are independently substituted or unsubstituted alkylor substituted or unsubstituted aryl. R is substituted or unsubstitutedlower alkyl, substituted or unsubstituted lower heteroalkyl, substitutedor unsubstituted lower cycloalkyl, substituted or unsubstituted lowerheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted lower heteroaryl. X is hydrogen, substituted orunsubstituted lower alkyl, or substituted or unsubstituted lowerheteroalkyl.

In another aspect, there is provided a method of treating a viraldisease in a subject, including administering to a subject in needthereof a therapeutically effective amount of a compound of Formula (I).

In another aspect, there is provided a method for treating cancer in asubject, including administering to a subject in need thereof atherapeutically effective amount of a compound of Formula (I).

In another aspect, there is provided a method for killing or inhibitingthe growth of a transformed cell, including contacting a transformedcell with a therapeutically effective amount of a compound of Formula(I).

In another aspect, there is provided a method for treating aproliferative disorder in a subject, including administering to asubject in need thereof a therapeutically effective amount of a compoundof Formula (I).

In another aspect, there is provided a pharmaceutical composition whichincludes a compound according to Formula (I), and a pharmaceuticallyacceptable excipient.

In another aspect, there is provided a method for synthesis of acompound with structure of Formula (I) according to Scheme 2 disclosedherein. The method includes contacting a protected nucleoside B_(Nuc)with structure of Formula (2-1) with an ester with structure of Formula(2-2) in the presence of a strong base under conditions suitable toafford a monoester with structure of Formula (2-3); and reacting theafforded monoester with L-OH in the presence of a coupling agent,thereby synthesizing a compound with structure of Formula (I).

In another aspect, there is provided a compound of Formula (Ia), or apharmaceutically acceptable salt, hydrate, solvate or crystalline formthereof:

For Formula (Ia), B_(Nuc(a)) can be a naturally occurring purine, anaturally occurring pyrimidine, a non-naturally occurring purine or anon-naturally occurring pyrimidine; L^(a) can be an unsubstituted C₁₂₋₂₄alkyl, an unsubstituted C₁₃₋₂₉ heteroalkyl or a substituted glycerylmoiety, wherein the glyceryl moiety can be substituted with one or moregroups selected from an unsubstituted C₁₃₋₂₉ alkyl, an unsubstitutedC₁₃₋₂₉ heteroalkyl, a substituted or unsubstituted aryl(C₁₋₆ alkyl), asubstituted or unsubstituted heteroaryl(C₁₋₆ alkyl) and a substituted orunsubstituted heterocycloalkyl(C₁₋₆ alkyl); R^(a) can be selected froman unsubstituted C₁₋₆ alkyl, a substituted or unsubstituted aryl, asubstituted or unsubstituted heteroaryl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl(C₁₋₆ alkyl), asubstituted or unsubstituted heteroaryl(C₁₋₆ alkyl) and a substituted orunsubstituted heterocycloalkyl(C₁₋₆ alkyl); and X^(a) can be hydrogen,an unsubstituted C₁₋₆ alkyl, a halogen substituted C₁₋₆ alkyl, a hydroxysubstituted C₁₋₆ alkyl or an unsubstituted C₁₋₆ alkoxy.

In another aspect, there is provided a pharmaceutical composition thatcan include an effective amount of a compound as disclosed herein (forexample, a compound of Formula (Ia)), or a pharmaceutically acceptablesalt, hydrate, solvate or crystalline form thereof, and apharmaceutically acceptable excipient.

In another aspect, there is provided a compound as disclosed herein (forexample, a compound of Formula (Ia)), or a pharmaceutically acceptablesalt, hydrate, solvate or crystalline form thereof, for use in treatinga viral disease in a subject, wherein the viral disease can be selectedfrom human papilloma virus, HIV, hepatitis B virus, hepatitis C virus,variola virus, vaccinia virus, an adenovirus, a cytomegalovirus, herpessimplex virus 1, herpes simplex virus 2, Epstein Barr virus, BK virus,JC virus, feline leukemia virus and feline immunodeficiency virus.

In another aspect, there is provided a compound as disclosed herein (forexample, a compound of Formula (Ia)), or a pharmaceutically acceptablesalt, hydrate, solvate or crystalline form thereof, for use in treatingcancer of the cervix in a subject.

In another aspect, there is provided a compound as disclosed herein, ora pharmaceutically acceptable salt, hydrate, solvate or crystalline formthereof, for use in inhibiting growth of a cell transformed by a virus,wherein the virus can be selected from human papilloma virus, HIV,hepatitis B virus, hepatitis C virus, variola virus, vaccinia virus, anadenovirus, a cytomegalovirus, herpes simplex virus 1, herpes simplexvirus 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virusand feline immunodeficiency virus.

In another aspect, there is provided a compound as disclosed herein (forexample, a compound of Formula (Ia)), or a pharmaceutically acceptablesalt, hydrate, solvate or crystalline form thereof, in the preparationof a medicament for treating a viral disease in a subject, wherein theviral disease can be selected from human papilloma virus, HIV, hepatitisB virus, hepatitis C virus, variola virus, vaccinia virus, anadenovirus, a cytomegalovirus, herpes simplex virus 1, herpes simplexvirus 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virusand feline immunodeficiency virus.

In another aspect, there is provided use of a compound as disclosedherein (for example, a compound of Formula (Ia)), or a pharmaceuticallyacceptable salt, hydrate, solvate or crystalline form thereof, in thepreparation of a medicament for treating cancer of the cervix in asubject.

In another aspect, there is provided use of a compound as disclosedherein (for example, a compound of Formula (Ia)), or a pharmaceuticallyacceptable salt, hydrate, solvate or crystalline form thereof, in thepreparation of a medicament for inhibiting growth of a cell transformedby a virus, wherein the virus can be selected from human papillomavirus, HIV, hepatitis B virus, hepatitis C virus, variola virus,vaccinia virus, an adenovirus, a cytomegalovirus, herpes simplex virus1, herpes simplex virus 2, Epstein Barr virus, BK virus, JC virus,feline leukemia virus and feline immunodeficiency virus.

In another aspect, there is provided a method of synthesis of a compoundwith structure of Formula (Ia).

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE provides a chromatogram of compound 1a (fast-eluting) andcompound 1b (slow eluting), as described in Example 2. X-axis: time(min); Y-axis (milli-absorption units, mAu). Solvent: 50:50:0.1Water:Acetonitrile:TFA.

DETAILED DESCRIPTION Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

As used herein, the term “alkyl,” by itself or as part of anothersubstituent, means, unless otherwise stated, and includes a straight(i.e., unbranched) or branched chain, or combination thereof, which maybe fully saturated, mono- or polyunsaturated and can include di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons). Alkyl is an uncyclized chain.Examples of saturated hydrocarbon radicals include, but are not limitedto, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl,isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

An unsaturated alkyl group is one having one or more double bonds (an“alkenyl group”) or triple bonds (an “alkynyl group”). Examples ofunsaturated alkyl groups include, but are not limited to, the alkenylgroups vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), and the alkynyl groups ethynyl, 1-and 3-propynyl, 3-butynyl, and the higher homologs and isomers.

An alkoxy is an alkyl attached to the remainder of the molecule via anoxygen linker (—O—).

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, or 10 or fewercarbon atoms. A “lower alkyl” or “lower alkylene” is a shorter chainalkyl or alkylene group, generally having eight or fewer carbon atoms.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, consisting of at least one carbon atom and atleast one heteroatom selected from the group consisting of O, N, P, Si,and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized, and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N, P, S, and Si may be placed at any interior positionof the heteroalkyl group or at the position at which the alkyl group isattached to the remainder of the molecule. Heteroalkyl is an uncyclizedchain. Examples include, but are not limited to: —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,—CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up to two heteroatomsmay be consecutive, such as, for example, —CH₂—NH—OCH₃.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—.

As described above, heteroalkyl groups, as used herein, include thosegroups that are attached to the remainder of the molecule through aheteroatom, such as —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl andheteroalkyl are not aromatic. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

A “cycloalkylene” and a “heterocycloalkylene,” alone or as part ofanother substituent, means a divalent radical derived from a cycloalkyland heterocycloalkyl, respectively.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R* where R* is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring.

The term “heteroaryl” refers to aryl groups (or rings) that contain fromone to four heteroatoms selected from N, O, and S, wherein the nitrogenand sulfur atoms are optionally oxidized, and the nitrogen atom(s) areoptionally quaternized. Thus, the term “heteroaryl” includes fused ringheteroaryl groups (i.e., multiple rings fused together wherein at leastone of the fused rings is a heteroaromatic ring). A 5,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 5members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers totwo rings fused together, wherein one ring has 6 members and the otherring has 6 members, and wherein at least one ring is a heteroaryl ring.And a 6,5-fused ring heteroarylene refers to two rings fused together,wherein one ring has 6 members and the other ring has 5 members, andwherein at least one ring is a heteroaryl ring. A heteroaryl group canbe attached to the remainder of the molecule through a carbon orheteroatom. Non-limiting examples of aryl and heteroaryl groups includephenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl,2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl,5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below. An “arylene” and a“heteroarylene,” alone or as part of another substituent, mean adivalent radical derived from an aryl and heteroaryl, respectively.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” [e.g., aryl(C₁₋₆alkyl)] is meant to include those radicals in which an aryl group isattached to an alkyl group (e.g., benzyl (Bn), phenethyl, pyridylmethyl,and the like) including those alkyl groups in which a carbon atom (e.g.,a methylene group) has been replaced by, for example, an oxygen atom(e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, andthe like). Thus, the term “heteroarylalkyl” [e.g., heteroaryl(C₁₋₆alkyl)] refers to those radicals in which a heteroaryl group is attachedto an alkyl group. The term “heterocycloalkylalkyl” [e.g.,heterocycloalkyl(C₁₋₆ alkyl)] refers to those radicals in which aheterocycloalkyl is attached to an alkyl group.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylsulfonyl,” as used herein, means a moiety having theformula —S(O₂)—R′, where R′ is an alkyl group as defined above. R′ mayhave a specified number of carbons (e.g., “C₁-C₄ alkylsulfonyl”).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of theindicated radical. Preferred substituents for each type of radical areprovided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN, and—NO₂ in a number ranging from zero to (2m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″, R′″, and R″″ eachpreferably independently refer to hydrogen, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g.,aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl,alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compoundincludes more than one R group, for example, each of the R groups isindependently selected as are each R′, R″, R′″, and R″″ group when morethan one of these groups is present. When R′ and R″ are attached to thesame nitrogen atom, they can be combined with the nitrogen atom to forma 4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ includes, but isnot limited to, 1-pyrrolidinyl and 4-morpholinyl. From the abovediscussion of substituents, one of skill in the art will understand thatthe term “substituted alkyl” is meant to include groups including carbonatoms bound to groups other than hydrogen groups, such as haloalkyl(e.g., —CF₃ and —CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃,—C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂,fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in a number ranging fromzero to the total number of open valences on the aromatic ring system;and where R′, R″, R′″, and R″″ are preferably independently selectedfrom hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. When acompound includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″, and R″″ groupswhen more than one of these groups is present.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In embodiments, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)-B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′— (C″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R′″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, oxo, halogen, unsubstituted        alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl,        unsubstituted heterocycloalkyl, unsubstituted aryl,        unsubstituted heteroaryl, and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo, —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, halogen,            unsubstituted alkyl, unsubstituted heteroalkyl,            unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,            unsubstituted aryl, unsubstituted heteroaryl, and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            and heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo, —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, halogen,                unsubstituted alkyl, unsubstituted heteroalkyl,                unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, unsubstituted                heteroaryl, and            -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,                aryl, or heteroaryl, substituted with at least one                substituent selected from: oxo, —OH, —NH₂, —SH, —CN,                —CF₃, —NO₂, halogen, unsubstituted alkyl, unsubstituted                heteroalkyl, unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, and unsubstituted                heteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₉ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 30 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In embodiments, each substituted group described in the compounds hereinis substituted with at least one substituent group. More specifically,in embodiments, each substituted alkyl, substituted heteroalkyl,substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl,substituted heteroaryl, substituted alkylene, substitutedheteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In embodiments, at least one or all ofthese groups are substituted with at least one size-limited substituentgroup. In embodiments, at least one or all of these groups aresubstituted with at least one lower substituent group.

In embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₃₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 30 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In embodimentsof the compounds herein, each substituted or unsubstituted alkylene is asubstituted or unsubstituted C₁-C₃₀ alkylene, each substituted orunsubstituted heteroalkylene is a substituted or unsubstituted 2 to 30membered heteroalkylene, each substituted or unsubstituted cycloalkyleneis a substituted or unsubstituted C₃-C₈ cycloalkylene, each substitutedor unsubstituted heterocycloalkylene is a substituted or unsubstituted 3to 8 membered heterocycloalkylene, each substituted or unsubstitutedarylene is a substituted or unsubstituted C₆-C₁₀ arylene, and/or eachsubstituted or unsubstituted heteroarylene is a substituted orunsubstituted 5 to 10 membered heteroarylene.

In embodiments, each substituted or unsubstituted alkyl is a substitutedor unsubstituted C₁-C₈ alkyl, each substituted or unsubstitutedheteroalkyl is a substituted or unsubstituted 2 to 8 memberedheteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds described herein containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts includesodium, potassium, calcium, ammonium, organic amino, or magnesium salt,or a similar salt. When compounds described herein contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like (see, for example, Bergeet al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977,66:1-19). Certain specific compounds described herein contain both basicand acidic functionalities that allow the compounds to be converted intoeither base or acid addition salts.

Thus, the compounds described herein [for example, a compound of Formula(I) and/or a compound of Formula (Ia)] may exist as salts, such as withpharmaceutically acceptable acids. Examples of such salts includehydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates,(−)-tartrates, or mixtures thereof including racemic mixtures),succinates, benzoates, and salts with amino acids such as glutamic acid.These salts may be prepared by methods known to those skilled in theart.

The neutral forms of the compounds can be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents.

In addition to salt forms, compounds described herein [for example, acompound of Formula (I) and/or a compound of Formula (Ia)] can be in aprodrug form. Prodrugs of the compounds described herein are thosecompounds that readily undergo chemical changes under physiologicalconditions to provide a compound described herein. Additionally,prodrugs can be converted to a compounds described herein by chemical orbiochemical methods in an ex vivo environment. For example, prodrugs canbe slowly converted to a compounds described herein when placed in atransdermal patch reservoir with a suitable enzyme or chemical reagent.The term “promoiety” is meant to refer to a chemical entity reversiblyattached to the drug that improves an aspect of drug performance bymasking a problematic functional group.

Certain compounds described herein [for example, a compound of Formula(I) and/or a compound of Formula (Ia)] can exist in unsolvated forms aswell as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassed.Certain compounds described herein [for example, a compound of Formula(I) and/or a compound of Formula (Ia)] may exist in multiple crystallineor amorphous forms. In general, all physical forms are equivalent forthe uses contemplated and are intended.

Certain compounds described herein [for example, a compound of Formula(I) and/or a compound of Formula (Ia)] can possess asymmetric atoms(optical centers) or double bonds; the racemates, diastereomers,tautomers, geometric isomers, and individual isomers are encompassed.The compounds described herein [for example, a compound of Formula (I)and/or a compound of Formula (Ia)] do not include those that are knownin the art to be too unstable to synthesize and/or isolate.

The compounds described herein [for example, a compound of Formula (I)and/or a compound of Formula (Ia)] may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds, whether radioactive or not, are encompassed.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

Compounds

In a first aspect, there is provided a compound with structure ofFormula (I):

or stereoisomer, salt, hydrate, solvate, or crystalline form thereof.For the compound with structure of Formula (I), B_(Nuc) is a naturallyoccurring purine or pyrimidine base, or analog thereof; L is alipophilic promoiety, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, or O-substituted glyceryl having the formula—CH₂CH(OR¹)—CH₂(OR²) (II), wherein R¹ and R² are independentlysubstituted or unsubstituted alkyl, or substituted or unsubstitutedaryl; R is substituted or unsubstituted lower alkyl, substituted orunsubstituted lower heteroalkyl, substituted or unsubstituted lowercycloalkyl, substituted or unsubstituted lower heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstituted lowerheteroaryl; and X is hydrogen, substituted or unsubstituted lower alkyl,or substituted or unsubstituted lower heteroalkyl.

In embodiments, the compound is a stereoisomer with the structure ofFormula (I). In embodiments, the compound is a salt of a compound withthe structure of Formula (I). In embodiments, the compound is a solvateof a compound with the structure of Formula (I). In embodiments, thecompound is a crystalline form of a compound with the structure ofFormula (I).

The terms “naturally occurring purine or pyrimidine base” and the likerefer, in the usual and customary sense as employed in the art, topurine or pyrimidine bases, e.g., guanine, adenine, cytosine, thymine,uracil, or 2,6-diaminopurine. Attachment of the naturally occurringpurine or pyrimidine base can be at any available site, e.g.,guanin-9-yl, adenine-9-yl, cytosine-1-yl, thymin-1-yl, uracil-1-yl,2,6-diaminopurin-9-yl, and the like. When attached to the remainder ofthe compounds described herein, the naturally occurring purine orpyrimidine base is in monovalent from (the form of a chemical moiety orsubstituent as known in the art).

The terms “analog of naturally occurring purine or pyrimidine base” andthe like refer, in the usual and customary sense, to a chemical analogof a naturally occurring purine or pyrimidine base, as known in the art.When attached to the remainder of the compounds described herein, theanalog of naturally occurring purine or pyrimidine base is in monovalentfrom (the form of a chemical moiety or substituent as known in the art).

Accordingly, in embodiments, B_(Nuc) is a naturally occurring purine orpyrimidine base. In embodiments, B_(Nuc) is a naturally occurring purinebase. In embodiments, B_(Nuc) is a naturally occurring pyrimidine base.In embodiments, B_(Nuc) is an analog of a naturally occurring purine orpyrimidine base. In embodiments, B_(Nuc) is an analog of a naturallyoccurring base. In embodiments, B_(Nuc) is an analog of a naturallyoccurring pyrimidine base.

The terms “lipophilic promoiety” and the like refer to a chemical moietywhich imparts increased lipophilicity when incorporated into a compoundwith structure of Formula (I). In embodiments, the lipophilic promoietyis a substituted or unsubstituted C₈₋₂₄ alkyl. In embodiments, thelipophilic promoiety is a substituted or unsubstituted C₈₋₂₄heteroalkyl. In embodiments, the lipophilic promoiety is a substitutedor unsubstituted C₈₋₂₄ alkoxyalkyl. Exemplary lipophilic promoietiesinclude glyceryl moieties having substituted or unsubstituted alkyl,and/or substituted or unsubstituted aryl substituents. In embodiments,substitution at a glyceryl moiety is via O-substitution with asubstituted or unsubstituted alkyl, and/or via 0-substitution with asubstituted or unsubstituted aryl. Thus, the lipophilic promoiety, L,imparts lipophilicity and therefore may include glyceryl ether linkedcompounds (e.g., 1-O-octadecyl-2-O-benzyl) wherein the hydrogens of theglyceryl hydroxyls are replaced with substituted or unsubstituted alkylor substituted or unsubstituted aryl groups that do not imparthydrophilicity, and the carbons atoms of the glyceryl are not furthersubstituted. In some embodiments, L is an O-substituted glyceryl havingthe formula —CH₂CH(OR¹)—CH₂(OR²) (II), wherein R¹ and R² areindependently a substituted or unsubstituted alkyl or a substituted orunsubstituted aryl.

In some embodiments, L is a substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, or an O-substituted glycerylhaving the formula —CH₂CH(OR¹)—CH₂(OR²) (II), wherein R¹ and R² areindependently a substituted or unsubstituted alkyl or a substituted orunsubstituted aryl. In embodiments, L is an O-substituted glyceryl. Inone embodiment L is 1-O-alkyl-2-O-benzyl-sn-glyceryl. In embodiments, Lis 1-O-octadecyl-2-O-benzyl-sn-glyceryl. In embodiments, L is anunsubstituted alkyl. In embodiments, L is a size-limited unsubstitutedalkyl. In embodiments, L is C₈₋₂₄ alkyl. In embodiments, L is anunsubstituted heteroalkyl. In embodiments, L is a size-limitedunsubstituted heteroalkyl. In embodiments, L is C₈₋₂₄ heteroalkyl. Inembodiments, L is an unsubstituted alkoxyoalkyl. In embodiments, L is asize-limited unsubstituted alkoxyalkyl. In embodiments, L is C₈₋₂₄alkoxyalkyl.

In embodiments, R is a substituted or unsubstituted lower alkyl, asubstituted or unsubstituted lower heteroalkyl, a substituted orunsubstituted lower cycloalkyl, a substituted or unsubstituted lowerheterocycloalkyl, a substituted or unsubstituted aryl, or a substitutedor unsubstituted lower heteroaryl. In embodiments, R is a substituted orunsubstituted lower alkyl. In embodiments, R is a substituted orunsubstituted lower heteroalkyl. In embodiments, R is an O-substitutedglyceryl having the formula —CH₂CH(OR³)—CH₂(OR⁴) (III), wherein R³ andR⁴ are independently a substituted or unsubstituted alkyl or asubstituted or unsubstituted aryl. In embodiments, R is a substituted orunsubstituted lower cycloalkyl. In embodiments, R is a substituted orunsubstituted lower heterocycloalkyl. In embodiments, R is a substitutedor unsubstituted hexopyranosyl. In embodiments, R is an unsubstitutedhexopyranosyl. In embodiments, R is a substituted or unsubstituted aryl.In embodiments, R is a substituted or unsubstituted lower heteroaryl. Inembodiments, R is an unsubstituted lower alkyl. In embodiments, R is anunsubstituted lower heteroalkyl. In embodiments, R is an unsubstitutedlower cycloalkyl. In embodiments, R is an unsubstituted lowerheterocycloalkyl. In embodiments, R is an unsubstituted aryl. Inembodiments, R is an unsubstituted lower heteroaryl. In embodiments, Ris a size-limited substituted or unsubstituted lower cycloalkyl. Inembodiments, R is a size-limited substituted or unsubstituted lowerheterocycloalkyl. In embodiments, R is a size-limited substituted orunsubstituted aryl. In embodiments, R is a size-limited substituted orunsubstituted lower heteroaryl. In embodiments, R is C₁-s substituted orunsubstituted alkyl. In embodiments, R is C₁₋₈s substituted orunsubstituted heteroalkyl. In embodiments, R is C₄-8 substituted orunsubstituted cycloalkyl. In embodiments, R is C₄-8 substituted orunsubstituted heterocycloalkyl. In embodiments, R is C₆-10 substitutedor unsubstituted aryl. In embodiments, R is C₆₋₁₀ substituted orunsubstituted heteroaryl. In embodiments, R is C₁₋₈ unsubstituted alkyl.In embodiments, R is C₂₋₈ unsubstituted heteroalkyl. In embodiments, Ris C₄₋₈ unsubstituted cycloalkyl. In embodiments, R is C₄₋₈unsubstituted heterocycloalkyl. In embodiments, R is C₆₋₁₀ unsubstitutedaryl. In embodiments, R is C₆₋₁₀ unsubstituted heteroaryl.

In embodiments, R is a substituted or unsubstituted phenyl, asubstituted or unsubstituted naphthyl, a substituted or unsubstitutedbenzyl, a substituted or unsubstituted glyceryl, or a substituted orunsubstituted hexopyranosyl. In embodiments, R is a substituted phenyl.In embodiments, R is a substituted naphthyl. In embodiments, R is asubstituted benzyl. In embodiments, R is a substituted glyceryl. Inembodiments, R is a substituted hexopyranosyl. In embodiments, R is anunsubstituted phenyl. In embodiments, R is an unsubstituted naphthyl. Inembodiments, R is an unsubstituted benzyl. In embodiments, R is anunsubstituted glyceryl. In embodiments, R is an unsubstitutedhexopyranosyl.

In embodiments, X is hydrogen, a substituted or unsubstituted loweralkyl, or a substituted or unsubstituted lower heteroalkyl. Inembodiments, X is hydrogen. In embodiments, X is a substituted orunsubstituted lower alkyl. In embodiments, X is a substituted orunsubstituted lower heteroalkyl. In embodiments, X is an unsubstitutedlower alkyl. In embodiments, X is an unsubstituted lower heteroalkyl. Inembodiments, X is a size-limited substituted or unsubstituted alkyl. Inembodiments, X is a size-limited substituted or unsubstitutedheteroalkyl. In embodiments, X is a size-limited unsubstituted alkyl. Inembodiments, X is a size-limited unsubstituted heteroalkyl. Inembodiments, X is methyl. In embodiments, X is methoxymethyl. Inembodiments, X is hydroxymethyl. In embodiments, X is fluoromethyl.

In embodiments, the compound with structure of Formula (I) has thestructure of Formula (I-1):

For the compound with structure of Formula (I-1), B_(Nuc) is asdescribed for any of the embodiments of the compound of Formula (I)disclosed herein.

In embodiments, L is as described for any of the embodiments of thecompound of Formula (I) described herein. In embodiments, L isoctadecyloxyethyl, hexadecyloxypropyl, or1-O-octadecyl-2-O-benzyl-sn-glyceryl. In embodiments, L isoctadecyloxyethyl. In embodiments, L is hexadecyloxypropyl. Inembodiments, L is 1-O-octadecyl-2-O-benzyl-sn-glyceryl.

In embodiments, R is as described for any of the embodiments of thecompound of Formula (I) described herein. In embodiments, R is asubstituted or unsubstituted phenyl, a substituted or unsubstitutednaphthyl, a substituted or unsubstituted benzyl, a substituted orunsubstituted glyceryl, or a substituted or unsubstituted hexopyranosyl.In embodiments, R is a substituted phenyl. In embodiments, R is asubstituted naphthyl. In embodiments, R is a substituted benzyl. Inembodiments, R is a substituted glyceryl. In embodiments, R is asubstituted hexopyranosyl. In embodiments, R is an unsubstituted phenyl.In embodiments, R is an unsubstituted naphthyl. In embodiments, R is anunsubstituted benzyl. In embodiments, R is an unsubstituted glyceryl. Inembodiments, R is an unsubstituted hexopyranosyl.

In embodiments, the compound with structure of Formula (I) has thestructure of Formula (I-2):

For the compound with structure of Formula (I-2), in one embodimentB_(Nuc) is as described for any of the embodiments of the compound ofFormulae (I)-(I-1) disclosed herein.

In embodiments, L is as described for any of the embodiments of thecompound of Formulae (I)-(I-1) described herein.

In embodiments, R is as described for any of the embodiments of thecompound of Formulae (I)-(I-1) described herein.

In embodiments, the compound with structure of Formula (I) has thestructure of Formula (I-3):

For the compound with structure of Formula (I-3), in one embodimentB_(Nuc) is as described for any of the embodiments of the compound ofFormulae (I)-(I-2) disclosed herein.

In embodiments, L is as described for any of the embodiments of thecompound of Formulae (I)-(I-2) described herein.

In embodiments, R is as described for any of the embodiments of thecompound of Formulae (I)-(I-2) described herein.

In embodiments, the compound with structure of Formula (I) has thestructure of Formula (I-4):

For the compound with structure of Formula (I-4), in one embodimentB_(Nuc) is as described for any of the embodiments of the compound ofFormulae (I)-(I-3) disclosed herein.

In embodiments, L is as described for any of the embodiments of thecompound of Formulae (I)-(I-3) described herein.

In embodiments, R is as described for any of the embodiments of thecompound of Formulae (I)-(I-3) described herein.

In embodiments, the compound with structure of Formula (I) has thestructure of Formula (I-5):

For the compound with structure of Formula (I-5), in one embodimentB_(Nuc) is as described for any of the embodiments of the compound ofFormulae (I)-(I-4) disclosed herein.

In embodiments, L is as described for any of the embodiments of thecompound of Formulae (I)-(I-4) described herein.

In embodiments, R is as described for any of the embodiments of thecompound of Formulae (I)-(I-4) described herein.

In another aspect, there is provided a compound of Formula (Ia), or apharmaceutically acceptable salt, hydrate, solvate or crystalline formthereof:

For this aspect, B_(Nuc(a)) can be a naturally occurring purine, anaturally occurring pyrimidine, a non-naturally occurring purine or anon-naturally occurring pyrimidine. L^(a) can be an unsubstituted C₁₂₋₂₄alkyl, an unsubstituted C₁₃₋₂₉ heteroalkyl or a substituted glycerylmoiety. The glyceryl moiety may be substituted with one or more groupsselected from an unsubstituted C₁₃₋₂₉ alkyl, an unsubstituted C₁₃₋₂₉heteroalkyl, a substituted or unsubstituted aryl(C₁₋₆ alkyl), asubstituted or unsubstituted heteroaryl(C₁₋₆ alkyl) and a substituted orunsubstituted heterocycloalkyl(C₁₋₆ alkyl). R^(a) can be selected froman unsubstituted C₁₋₆ alkyl, a substituted or unsubstituted aryl, asubstituted or unsubstituted heteroaryl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl(C₁₋₆ alkyl), asubstituted or unsubstituted heteroaryl(C₁₋₆ alkyl) and a substituted orunsubstituted heterocycloalkyl(C₁₋₆ alkyl). X^(a) can be hydrogen, anunsubstituted C₁₋₆ alkyl, a halogen substituted C₁₋₆ alkyl, a hydroxysubstituted C₁₋₆ alkyl or an unsubstituted C₁₋₆ alkoxy.

In embodiments, X^(a) can be hydrogen, an unsubstituted C₁₋₆ alkyl, ahalogen substituted C₁₋₆ alkyl, a hydroxy substituted C₁₋₆ alkyl or anunsubstituted C₁₋₆ alkoxy. In embodiments, X^(a) can be hydrogen. Inembodiments, X^(a) can be an unsubstituted C₁₋₆ alkyl. In embodiments,X^(a) can be methyl. In embodiments, X^(a) can be a hydroxy substitutedC₁₋₆ alkyl. In embodiments, X^(a) can be —CH₂OH. In embodiments, X canbe an unsubstituted C₁₋₆ alkoxy. In embodiments, X^(a) can be methoxy.In embodiments, X^(a) can be a halogen substituted C₁₋₆ alkyl. Inembodiments, X^(a) can be a fluoro substituted C₁₋₆ alkyl. Inembodiments, X^(a) can be —CH₂F.

Further to any embodiment above, in embodiments L^(a) can be anunsubstituted C₁₃₋₂₉ heteroalkyl. In embodiments, L^(a) can have thestructure —(CH₂)₁₋₆—O—(CH₂)₁₁₋₂₁—CH₃. In embodiments, L^(a) can have thestructure —(CH₂)₂—O—(CH₂)₁₇—CH₃. In embodiments, L^(a) can have thestructure —(CH₂)₃—O—(CH₂)₁₅—CH₃. In embodiments, L^(a) can have thestructure —(CH₂)₁₋₆—O—(CH₂)₁₀₋₂₀—(CHCH₃)—CH₃.

Further to any embodiment above, in embodiments L^(a) can be asubstituted glyceryl moiety. In embodiments, L^(a) can have thestructure —(CH₂)—CH(OR^(a1))—(CH₂)—O(CH₂)₁₁₋₂₁—CH₃, wherein R^(a1) canbe a substituted or unsubstituted aryl(C₁₋₆ alkyl), a substituted orunsubstituted heteroaryl(C₁₋₆ alkyl) or a substituted or unsubstitutedheterocycloalkyl(C₁₋₆ alkyl). In embodiment, R^(a1) can be a substitutedaryl(C₁₋₆ alkyl). In embodiment, R^(a1) can be an unsubstitutedaryl(C₁₋₆ alkyl). In embodiment, R^(a1) can be a substitutedheteroaryl(C₁₋₆ alkyl). In embodiment, R^(a1) can be an unsubstitutedheteroaryl(C₁₋₆ alkyl)). In embodiment, R^(a1) can be a substitutedheterocycloalkyl(C₁₋₆ alkyl). In embodiment, R^(a1) can be anunsubstituted heterocycloalkyl(C₁₋₆ alkyl).

In embodiments, L^(a) can have the structure

Further to any embodiment of the compound of Formula (Ia), inembodiments R^(a) can be a substituted or unsubstituted aryl. Inembodiments, the substituted aryl can be a substituted phenyl. Inembodiments, the unsubstituted aryl can be an unsubstituted phenyl. Inembodiments, the substituted aryl can be a substituted naphthyl. Inembodiments, the unsubstituted aryl can be an unsubstituted naphthyl.

Further to any embodiment of the compound of Formula (Ia), inembodiments R^(a) can be a substituted or unsubstituted aryl(C₁₋₆alkyl). In embodiments, the substituted aryl(C₁₋₆ alkyl) can be asubstituted benzyl. In embodiments, the unsubstituted aryl(C₁₋₆ alkyl)can be an unsubstituted benzyl.

Further to any embodiment of the compound of Formula (Ia), inembodiments R^(a) can be a substituted or unsubstitutedheterocycloalkyl(C₁₋₆ alkyl). In embodiments, the substituted orunsubstituted heterocycloalkyl(C₁₋₆ alkyl) is a substituted orunsubstituted galactosyl.

Further to any embodiment of the compound of Formula (Ia), inembodiments B_(Nuc(a)) can be a naturally occurring purine. Inembodiments, B_(Nuc(a)) can be a naturally occurring pyrimidine. Inembodiments, B_(Nuc(a)) can be a non-naturally occurring purine. Inembodiments, B_(Nuc(a)) can be a non-naturally occurring pyrimidine. Theterm “non-naturally occurring” and the like, in the context of purine orpyrimidine nucleoside B_(Nuc(a)) groups, refers to moieties having apurine or pyrimidine core and additional chemical modifications notfound in naturally occurring systems. Examples of purines includeadenine, guanine, hypoxanthine, xanthine, theobromine, caffeine, uricacid, isoguanine, 2,6-diaminopurine. Examples of pyrimidines includecytosine, thymine, and uracil.

In embodiments, B_(Nuc(a)) can be selected from:

In embodiments, a compound of Formula (Ia) can have the structure:

In embodiments, a compound of Formula (Ia) can have the structure:

In embodiments, a compound of Formula (Ia) can have the structure:

In embodiments, a compound of Formula (Ia) can have the structure:

In embodiments, a compound of Formula (Ia) can have the structure:

In embodiments, a compound of Formula (Ia) can have the structure:

In embodiments, the compound can be selected from:

or a pharmaceutically acceptable salt, hydrate, solvate or crystallineform of any of the foregoing.

As can be seen from Formulae (I) and (Ia), there are many embodiments.For example, there are disclosed embodiments directed to a compound ofFormula (I) and a compound of Formula (Ia) based on the identity of theacyclic nucleoside phosphonate scaffold. This is not intended to be anexplicit or implicit admission that the embodiments are independent ordistinct nor should it be interpreted as such. Rather, it is intended toconvey information so that the full breadth of Formulae (I) and (Ia) canbe understood. Furthermore, the following embodiments, and aspectsthereof, are not meant to be limiting on the full breadth of thestructure of Formula (I) and/or the structure of Formula (Ia).

Tables 1-10 following disclose structures contemplated herein. Thestructures of Tables 1-10 and are not intended to be limiting on thefull breadth of the contemplated compounds represented by the structureof Formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5) and (Ia). Moreover,it is contemplated that any one of the contemplated acyclic nucleosidephosphonate (ANP) scaffolds (PME-, (R)-PMP-, (S)-MPMP-, (S)-HPMP- and(S)-FPMP-) or their stereoisomers, can be used in combination with anyof the contemplated combinations of naturally occurring or modifiedpurine or pyrimidine base (B_(Nuc)/B_(Nuc(a))), L/L^(a) and R/R^(a).Additionally, as the phosphorus atom of the ANP diester is a potentialchiral center, it is understood that Rp and Sp (i.e., Cahn-Ingold-Prelognomenclature as known in the art) stereochemical configurations arepossible. Therefore, the structures below include stereochemicalconfigurations possible for phosphorus.

TABLE 1 Phosphonomethoxyethyl (PME) diester compounds

Cmpd No. B_(Nuc)/B_(Nuc(a)) L/L^(a) R/R^(a) Name  1-(Rp, guanin-9-yloctadecyloxyethyl benzyl benzyl octadecyloxyethyl 9-(2- sp)phosphonomethoxyethyl)guanine  1a guanin-9-yl octadecyloxyethyl benzylbenzyl octadecyloxyethyl 9-(2- (fast) phosphonomethoxyethyl)guanine  1bguanin-9-yl octadecyloxyethyl benzyl benzyl octadecyloxyethyl 9-(2-(slow) phosphonomethoxyethyl)guanine  2 adenine-9-yl octadecyloxyethylbenzyl benzyl octadecyloxyethyl 9-(2- phosphonomethoxyethyl)adenine  3cytosine-1-yl octadecyloxyethyl benzyl benzyl octadecyloxyethyl 1-(2-phosphonomethoxyethyl)cytosine  4 thymin-1-yl octadecyloxyethyl benzylbenzyl octadecyloxyethyl 1-(2- phosphonomethoxyethyl)thymine  5uracil-1-yl octadecyloxyethyl benzyl benzyl octadecyloxyethyl 9-(2-phosphonomethoxyethyl)uracil  6 2,6- octadecyloxyethyl benzyl benzyloctadecyloxyethyl 9-(2- diaminopurin- phosphonomethoxyethyl)-2,6- 9-yldiaminopurine  7 guanin-7-yl hexadecyloxypropyl benzyl benzylhexadecyloxypropyl 9-(2- phosphonomethoxyethyl)guanine  8 adenine-9-ylhexadecyloxypropyl benzyl benzyl hexadecyloxypropyl 9-(2-phosphonomethoxyethyl)adenine  9 cytosine-1-yl hexadecyloxypropyl benzylbenzyl hexadecyloxypropyl 1-(2- phosphonomethoxyethyl)cytosine 10thymin-1-yl hexadecyloxypropyl benzyl benzyl hexadecyloxypropyl 1-(2-phosphonomethoxyethyl)thymine 11 uracil-1-yl hexadecyloxypropyl benzylbenzyl hexadecyloxypropyl 9-(2- phosphonomethoxyethyl)uracil 12 2,6-hexadecyloxypropyl benzyl benzyl hexadecyloxypropyl 9-(2- diaminopurin-phosphonomethoxyethyl)-2,6- 9-yl diaminopurine 13 guanin-9-yl1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl- benzyl-snglyceryl sn glyceryl 9-(2- phosphonomethoxyethyl)guanine 14 adenine-9-yl1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl- benzyl-snglyceryl sn glyceryl 9-(2- phosphonomethoxyethyl)adenine 15cytosine-1-yl 1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-benzyl-sn glyceryl sn glyceryl 1-(2- phosphonomethoxyethyl)cytosine 16thymin-1-yl 1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-benzyl-sn glyceryl sn glyceryl 1-(2-phosphonomethoxy- ethyl)thymine 17uracil-1-yl 1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-snbenzyl-sn glyceryl glyceryl 9-(2-phosphonomethoxy- ethyl)uracil 18 2,6-1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-sndiaminopurin- benzyl-sn glyceryl glyceryl 9-(2-phosphonomethoxy- 9-ylethyl)-2,6-diaminopurine 19 guanin-9-yl octadecyloxyethyl phenyl phenyloctadecyloxyethyl 9-(2- phosphonomethoxyethyl)guanine 20 adenine-9-yloctadecyloxyethyl phenyl phenyl octadecyloxyethyl 9-(2-phosphonomethoxyethyl)adenine 21 cytosine-1-yl octadecyloxyethyl phenylphenyl octadecyloxyethyl 1-(2- phosphonomethoxyethyl)cytosine 22thymin-1-yl octadecyloxyethyl phenyl phenyl octadecyloxyethyl 1-(2-phosphonomethoxyethyl)thymine 23 uracil-1-yl octadecyloxyethyl phenylphenyl octadecyloxyethyl 9-(2- phosphonomethoxyethyl)uracil 24 2,6-octadecyloxyethyl phenyl phenyl octadecyloxyethyl 9-(2- diaminopurin-phosphonomethoxyethyl)-2,6- 9-yl diaminopurine 25 guanin-9-ylhexadecyloxypropyl phenyl phenyl hexadecyloxypropyl 9-(2-phosphonomethoxyethyl)guanine 26 adenine-9-yl hexadecyloxypropyl phenylphenyl hexadecyloxypropyl 9-(2- phosphonomethoxyethyl)adenine 27cytosine-1-yl hexadecyloxypropyl phenyl phenyl hexadecyloxypropyl 1-(2-phosphonomethoxyethyl)cytosine 28 thymin-1-yl hexadecyloxypropyl phenylphenyl hexadecyloxypropyl 1-(2- phosphonomethoxyethyl)thymine 29uracil-1-yl hexadecyloxypropyl phenyl phenyl hexadecyloxypropyl 9-(2-phosphonomethoxyethyl)uracil 30 2,6- hexadecyloxypropyl phenyl phenylhexadecyloxypropyl 9-(2- diaminopurin- phosphonomethoxyethyl)-2,6- 9-yldiaminopurine 31 guanin-9-yl 1-O-octadecyl-2-O- phenyl phenyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl 9-(2-phosphonomethoxyethyl)guanine 32 adenine-9-yl 1-O-octadecyl-2-O- phenylphenyl 1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl 9-(2-phosphonomethoxyethyl)adenine 33 cytosine-1-yl 1-O-octadecyl-2-O- phenylphenyl 1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl 1-(2-phosphonomethoxyethyl)cytosine 34 thymin-1-yl 1-O-octadecyl-2-O- phenylphenyl 1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl 1-(2-phosphonomethoxyethyl)thymine 35 uracil-1-yl 1-O-octadecyl-2-O- phenylphenyl 1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl 9-(2-phosphonomethoxyethyl)uracil 36 2,6- 1-O-octadecyl-2-O- phenyl phenyl1-O-octadecyl-2-O-benzyl-sn diaminopurin- benzyl-sn glyceryl glyceryl9-(2- 9-yl phosphonomethoxyethyl)-2,6- diaminopurine 37 guanin-9-yloctadecyloxyethyl ethyl ethyl octadecyloxyethyl 9-(2-phosphonomethoxyethyl)guanine 38 adenine-9-yl octadecyloxyethyl ethylethyl octadecyloxyethyl 9-(2- phosphonomethoxyethyl)adenine 39cytosine-1-yl octadecyloxyethyl ethyl ethyl octadecyloxyethyl 1-(2-phosphonomethoxyethyl)cytosine 40 thymin-1-yl octadecyloxyethyl ethylethyl octadecyloxyethyl 1-(2- phosphonomethoxyethyl)thymine 41uracil-1-yl octadecyloxyethyl ethyl ethyl octadecyloxyethyl 9-(2-phosphonomethoxyethyl)uracil 42 2,6- octadecyloxyethyl ethyl ethyloctadecyloxyethyl 9-(2- diaminopurin- phosphonomethoxyethyl)-2,6- 9-yldiaminopurine 43 guanin-9-yl hexadecyloxypropyl ethyl ethylhexadecyloxypropyl 9-(2- phosphonomethoxyethyl)guanine 44 adenine-9-ylhexadecyloxypropyl ethyl ethyl hexadecyloxypropyl 9-(2-phosphonomethoxyethyl)adenine 45 cytosine-1-yl hexadecyloxypropyl ethylethyl hexadecyloxypropyl 1-(2- phosphonomethoxyethyl)cytosine 46thymin-1-yl hexadecyloxypropyl ethyl ethyl hexadecyloxypropyl 1-(2-phosphonomethoxyethyl)thymine 47 uracil-1-yl hexadecyloxypropyl ethylethyl hexadecyloxypropyl 9-(2- phosphonomethoxyethyl)uracil 48 2,6-hexadecyloxypropyl ethyl ethyl hexadecyloxypropyl 9-(2- diaminopurin-phosphonomethoxyethyl)-2,6- 9-yl diaminopurine 49 guanin-9-yl1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 9-(2- phosphonomethoxyethyl)guanine 50 adenine-9-yl1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 9-(2- phosphonomethoxyethyl)adenine 51 cytosine-1-yl1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(2- phosphonomethoxyethyl)cytosine 52 thymin-1-yl1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(2- phosphonomethoxyethyl)thymine 53 uracil-1-yl1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 9-(2- phosphonomethoxyethyl)uracil 54 2,6-1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn diaminopurin-benzyl-sn glyceryl glyceryl 9-(2- 9-yl phosphonomethoxyethyl)-2,6-diaminopurine 55 guanin-9-yl octadecyloxyethyl galactosyl galactosyloctadecyloxyethyl 9-(2- phosphonomethoxyethyl)guanine 56 adenine-9-yloctadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 9-(2-phosphonomethoxyethyl)adenine 57 cytosine-1-yl octadecyloxyethylgalactosyl galactosyl octadecyloxyethyl 1-(2-phosphonomethoxyethyl)cytosine 58 thymin-1-yl octadecyloxyethylgalactosyl galactosyl octadecyloxyethyl 1-(2-phosphonomethoxyethyl)thymine 59 uracil-1-yl octadecyloxyethylgalactosyl galactosyl octadecyloxyethyl 9-(2-phosphonomethoxyethyl)uracil 60 2,6- octadecyloxyethyl galactosylgalactosyl octadecyloxyethyl 9-(2- diaminopurin-phosphonomethoxyethyl)-2,6- 9-yl diaminopurine 61 guanin-9-ylhexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl 9-(2-phosphonomethoxyethyl)guanine 62 adenine-9-yl hexadecyloxypropylgalactosyl galactosyl hexadecyloxypropyl 9-(2-phosphonomethoxyethyl)adenine 63 cytosine-1-yl hexadecyloxypropylgalactosyl galactosyl hexadecyloxypropyl 1-(2-phosphonomethoxyethyl)cytosine 64 thymin-1-yl hexadecyloxypropylgalactosyl galactosyl hexadecyloxypropyl 1-(2-phosphonomethoxyethyl)thymine 65 uracil-1-yl hexadecyloxypropylgalactosyl galactosyl hexadecyloxypropyl 9-(2-phosphonomethoxyethyl)uracil 66 2,6- hexadecyloxypropyl galactosylgalactosyl hexadecyloxypropyl 9-(2- diaminopurin-phosphonomethoxyethyl)-2,6- 9-yl diaminopurine 67 guanin-9-yl1-O-octadecyl-2-O- galactosyl galactosyl 1-O-octadecyl-2-O-benzyl-benzyl-sn glyceryl sn glyceryl 9-(2- phosphonomethoxyethyl)guanine 68adenine-9-yl 1-O-octadecyl-2-O- galactosyl galactosyl1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl sn glyceryl 9-(2-phosphonomethoxyethyl)adenine 69 cytosine-1-yl 1-O-octadecyl-2-O-galactosyl galactosyl 1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl snglyceryl 1-(2- phosphonomethoxyethyl)cytosine 70 thymin-1-yl1-O-octadecyl-2-O- galactosyl galactosyl 1-O-octadecyl-2-O-benzyl-benzyl-sn glyceryl sn glyceryl 1-(2- phosphonomethoxyethyl)thymine 71uracil-1-yl 1-O-octadecyl-2-O- galactosyl galactosyl1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl sn glyceryl 9-(2-phosphonomethoxyethyl)uracil 72 2,6- 1-O-octadecyl-2-O- galactosylgalactosyl 1-O-octadecyl-2-O-benzyl- diaminopurin- benzyl-sn glyceryl snglyceryl 9-(2- 9-yl phosphonomethoxyethyl)-2,6- diaminopurine

TABLE 2 (R)-phosphonomethoxypropyl [(R)-PMP] diester compounds

Cmpd No. B_(Nuc)/B_(Nuc(a)) L/L^(a) R/R^(a) Name 73 guanin-9-yloctadecyloxyethyl benzyl benzyl octadecyloxyethyl 9-(R)-[(2-phosphonomethoxy)propyl]guanine 74 adenine-9-yl octadecyloxyethyl benzylbenzyl octadecyloxyethyl 9-(R)-[(2- phosphonomethoxy)propyl]adenine 75cytosine-1-yl octadecyloxyethyl benzyl benzyl octadecyloxyethyl1-(R)-[(2- phosphonomethoxy)propyl]cytosine 76 thymin-1-yloctadecyloxyethyl benzyl benzyl octadecyloxyethyl 1-(R)-[(2-phosphonomethoxy)propyl]thymine 77 uracil-1-yl octadecyloxyethyl benzylbenzyl octadecyloxyethyl 1-(R)-[(2- phosphonomethoxy)propyl]uracil 782,6- octadecyloxyethyl benzyl benzyl octadecyloxyethyl 9-(R)-[(2-diaminopurin- phosphonomethoxy)propyl]2,6- 9-yl diaminopurine 79guanin-9-yl hexadecyloxypropyl benzyl benzyl hexadecyloxypropyl9-(R)-[(2- phosphonomethoxy)propyl]guanine 80 adenine-9-ylhexadecyloxypropyl benzyl benzyl hexadecyloxypropyl 9-(R)-[(2-phosphonomethoxy)propyl]adenine 81 cytosine-1-yl hexadecyloxypropylbenzyl benzyl hexadecyloxypropyl 1-(R)-[(2-phosphonomethoxy)propyl]cytosine 82 thymin-1-yl hexadecyloxypropylbenzyl benzyl hexadecyloxypropyl 1-(R)-[(2-phosphonomethoxy)propyl]thymine 83 uracil-1-yl hexadecyloxypropyl benzylbenzyl hexadecyloxypropyl 1-(R)-[(2- phosphonomethoxy)propyl]uracil 842,6- hexadecyloxypropyl benzyl benzyl hexadecyloxypropyl 9-(R)-[(2-diaminopurin- phosphonomethoxy)propyl]2,6- 9-yl diaminopurine 85guanin-9-yl 1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-snbenzyl-sn glyceryl glyceryl 9-(R)-[(2- phosphonomethoxy)propyl]guanine86 adenine-9-yl 1-O-octadecyl-2-O- benzyl benzyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl 9-(R)-[(2-phosphonomethoxy)propyl]adenine 87 cytosine-1-yl 1-O-octadecyl-2-O-benzyl benzyl 1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl1-(R)-[(2- phosphonomethoxy)propyl]cytosine 88 thymin-1-yl1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(R)-[(2- phosphonomethoxy)propyl]thymine 89uracil-1-yl 1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-snbenzyl-sn glyceryl glyceryl 1-(R)-[(2- phosphonomethoxy)propyl]uracil 902,6- 1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-sndiaminopurin- benzyl-sn glyceryl glyceryl 9-(R)-[(2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 91 guanin-9-yloctadecyloxyethyl phenyl phenyl octadecyloxyethyl 9-(R)-[(2-phosphonomethoxy)propyl]guanine 92 adenine-9-yl octadecyloxyethyl phenylphenyl octadecyloxyethyl 9-(R)-[(2- phosphonomethoxy)propyl]adenine 93cytosine-1-yl octadecyloxyethyl phenyl phenyl octadecyloxyethyl1-(R)-[(2- phosphonomethoxy)propyl]cytosine 94 thymin-1-yloctadecyloxyethyl phenyl phenyl octadecyloxyethyl 1-(R)-[(2-phosphonomethoxy)propyl]thymine 95 uracil-1-yl octadecyloxyethyl phenylphenyl octadecyloxyethyl 1-(R)-[(2- phosphonomethoxy)propyl]uracil 962,6- octadecyloxyethyl phenyl phenyl octadecyloxyethyl 9-(R)-[(2-diaminopurin- phosphonomethoxy)propyl]2,6- 9-yl diaminopurine 97guanin-9-yl hexadecyloxypropyl phenyl phenyl hexadecyloxypropyl9-(R)-[(2- phosphonomethoxy)propyl]guanine 98 adenine-9-ylhexadecyloxypropyl phenyl phenyl hexadecyloxypropyl 9-(R)-[(2-phosphonomethoxy)propyl]adenine 99 cytosine-1-yl hexadecyloxypropylphenyl phenyl hexadecyloxypropyl 1-(R)-[(2-phosphonomethoxy)propyl]cytosine 100 thymin-1-yl hexadecyloxypropylphenyl phenyl hexadecyloxypropyl 1-(R)-[(2-phosphonomethoxy)propyl]thymine 101 uracil-1-yl hexadecyloxypropylphenyl phenyl hexadecyloxypropyl 1-(R)-[(2-phosphonomethoxy)propyl]uracil 102 2,6- hexadecyloxypropyl phenyl phenylhexadecyloxypropyl 9-(R)-[(2- diaminopurin- phosphonomethoxy)propyl]2,6-9-yl diaminopurine 103 guanin-9-yl 1-O-octadecyl-2-O- phenyl phenyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl 9-(R)-[(2-phosphonomethoxy)propyl]guanine 104 adenine-9-yl 1-O-octadecyl-2-O-phenyl phenyl 1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl9-(R)-[(2- phosphonomethoxy)propyl]adenine 105 cytosine-1-yl1-O-octadecyl-2-O- phenyl phenyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(R)-[(2- phosphonomethoxy)propyl]cytosine 106thymin-1-yl 1-O-octadecyl-2-O- phenyl phenyl 1-O-octadecyl-2-O-benzyl-snbenzyl-sn glyceryl glyceryl 1-(R)-[(2- phosphonomethoxy)propyl]thymine107 uracil-1-yl 1-O-octadecyl-2-O- phenyl phenyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl 1-(R)-[(2-phosphonomethoxy)propyl]uracil 108 2,6- 1-O-octadecyl-2-O- phenyl phenyl1-O-octadecyl-2-O-benzyl-sn diaminopurin- benzyl-sn glyceryl glyceryl9-(R)-[(2- 9-yl phosphonomethoxy)propyl]2,6- diaminopurine 109guanin-9-yl octadecyloxyethyl ethyl ethyl octadecyloxyethyl 9-(R)-[(2-phosphonomethoxy)propyl]guanine 110 adenine-9-yl octadecyloxyethyl ethylethyl octadecyloxyethyl 9-(R)-[(2- phosphonomethoxy)propyl]adenine 111cytosine-1-yl octadecyloxyethyl ethyl ethyl octadecyloxyethyl 1-(R)-[(2-phosphonomethoxy)propyl]cytosine 112 thymin-1-yl octadecyloxyethyl ethylethyl octadecyloxyethyl 1-(R)-[(2- phosphonomethoxy)propyl]thymine 113uracil-1-yl octadecyloxyethyl ethyl ethyl octadecyloxyethyl 1-(R)-[(2-phosphonomethoxy)propyl]uracil 114 2,6- octadecyloxyethyl ethyl ethyloctadecyloxyethyl 9-(R)-[(2- diaminopurin- phosphonomethoxy)propyl]2,6-9-yl diaminopurine 115 guanin-9-yl hexadecyloxypropyl ethyl ethylhexadecyloxypropyl 9-(R)-[(2- phosphonomethoxy)propyl]guanine 116adenine-9-yl hexadecyloxypropyl ethyl ethyl hexadecyloxypropyl9-(R)-[(2- phosphonomethoxy)propyl]adenine 117 cytosine-1-ylhexadecyloxypropyl ethyl ethyl hexadecyloxypropyl 1-(R)-[(2-phosphonomethoxy)propyl]cytosine 118 thymin-1-yl hexadecyloxypropylethyl ethyl hexadecyloxypropyl 1-(R)-[(2-phosphonomethoxy)propyl]thymine 119 uracil-1-yl hexadecyloxypropyl ethylethyl hexadecyloxypropyl 1-(R)-[(2- phosphonomethoxy)propyl]uracil 1202,6- hexadecyloxypropyl ethyl ethyl hexadecyloxypropyl 9-(R)-[(2-diaminopurin- phosphonomethoxy)propyl]2,6- 9-yl diaminopurine 121guanin-9-yl 1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-snbenzyl-sn glyceryl glyceryl 9-(R)-[(2- phosphonomethoxy)propyl]guanine122 adenine-9-yl 1-O-octadecyl-2-O- ethyl ethyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl 9-(R)-[(2-phosphonomethoxy)propyl]adenine 123 cytosine-1-yl 1-O-octadecyl-2-O-ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl1-(R)-[(2- phosphonomethoxy)propyl]cytosine 124 thymin-1-yl1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(R)-[(2- phosphonomethoxy)propyl]thymine 125uracil-1-yl 1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-snbenzyl-sn glyceryl glyceryl 1-(R)-[(2- phosphonomethoxy)propyl]uracil126 2,6- 1-O-octadecyl-2-O- ethyl phenyl 1-O-octadecyl-2-O-benzyl-sndiaminopurin- benzyl-sn glyceryl glyceryl 9-(R)-[(2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 127 guanin-9-yloctadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 9-(R)-[(2-phosphonomethoxy)propyl]guanine 128 adenine-9-yl octadecyloxyethylgalactosyl galactosyl octadecyloxyethyl 9-(R)-[(2-phosphonomethoxy)propyl]adenine 129 cytosine-1-yl octadecyloxyethylgalactosyl galactosyl octadecyloxyethyl 1-(R)-[(2-phosphonomethoxy)propyl]cytosine 130 thymin-1-yl octadecyloxyethylgalactosyl galactosyl octadecyloxyethyl 1-(R)-[(2-phosphonomethoxy)propyl]thymine 131 uracil-1-yl octadecyloxyethylgalactosyl galactosyl octadecyloxyethyl 1-(R)-[(2-phosphonomethoxy)propyl]uracil 132 2,6- octadecyloxyethyl galactosylgalactosyl octadecyloxyethyl 9-(R)-[(2- diaminopurin-phosphonomethoxy)propyl]2,6- 9-yl diaminopurine 133 guanin-9-ylhexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl 9-(R)-[(2-phosphonomethoxy)propyl]guanine 134 adenine-9-yl hexadecyloxypropylgalactosyl galactosyl hexadecyloxypropyl 9-(R)-[(2-phosphonomethoxy)propyl]adenine 135 cytosine-1-yl hexadecyloxypropylgalactosyl galactosyl hexadecyloxypropyl 1-(R)-[(2-phosphonomethoxy)propyl]cytosine 136 thymin-1-yl hexadecyloxypropylgalactosyl galactosyl hexadecyloxypropyl 1-(R)-[(2-phosphonomethoxy)propyl]thymine 137 uracil-1-yl hexadecyloxypropylgalactosyl galactosyl hexadecyloxypropyl 1-(R)-[(2-phosphonomethoxy)propyl]uracil 138 2,6- hexadecyloxypropylgalactosyl galactosyl hexadecyloxypropyl 9-(R)- diaminopurin-[(2-phosphonomethoxy)propyl]2,6- 9-yl diaminopurine 139 guanin-9-yl1-O-octadecyl-2-O- galactosyl galactosyl 1-O-octadecyl-2-O-benzyl-benzyl-sn glyceryl sn glyceryl 9-(R)-[(2-phosphonomethoxy)propyl]guanine 140 adenine-9-yl 1-O-octadecyl-2-O-galactosyl galactosyl 1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl snglyceryl 9-(R)-[(2- phosphonomethoxy)propyl]adenine 141 cytosine-1-yl1-O-octadecyl-2-O- galactosyl galactosyl 1-O-octadecyl-2-O-benzyl-benzyl-sn glyceryl sn glyceryl 1-(R)-[(2-phosphonomethoxy)propyl]cytosine 142 thymin-1-yl 1-O-octadecyl-2-O-galactosyl galactosyl 1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl snglyceryl 1-(R)-[(2- phosphonomethoxy)propyl]thymine 143 uracil-1-yl1-O-octadecyl-2-O- galactosyl galactosyl 1-O-octadecyl-2-O-benzyl-benzyl-sn glyceryl sn glyceryl 1-(R)-[(2- phosphonomethoxy)propyl]uracil144 2,6- 1-O-octadecyl-2-O- galactosyl galactosyl1-O-octadecyl-2-O-benzyl- diaminopurin- benzyl-sn glyceryl sn glyceryl9-(R)-[(2- 9-yl phosphonomethoxy)propyl]2,6- diaminopurine

TABLE 3 (S)-3-methoxy-2-phosphonmethoxypropyl [(S)-MPMP] diestercompounds

Cmpd No. B_(Nuc)/B_(Nuc(a)) L/L^(a) R/R^(a) Name 145 guanin-9-yloctadecyloxyethyl benzyl benzyl octadecyloxyethyl 9-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]guanine 146 adenine-9-yl octadecyloxyethylbenzyl benzyl octadecyloxyethyl 9-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]adenine 147 cytosine-1-yl octadecyloxyethylbenzyl benzyl octadecyloxyethyl 1-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]cytosine 148 thymin-1-yl octadecyloxyethylbenzyl benzyl octadecyloxyethyl 1-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]thymine 149 uracil-1-yl octadecyloxyethyl benzylbenzyl octadecyloxyethyl 1-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]uracil 150 2,6- octadecyloxyethyl benzyl benzyloctadecyloxyethyl 9-(S)-[(3- diaminopurin- methoxy-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 151 guanin-9-ylhexadecyloxypropyl benzyl benzyl hexadecyloxypropyl 9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]guanine 152 adenine-9-ylhexadecyloxypropyl benzyl benzyl hexadecyloxypropyl 9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]adenine 153 cytosine-1-ylhexadecyloxypropyl benzyl benzyl hexadecyloxypropyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]cytosine 154 thymin-1-ylhexadecyloxypropyl benzyl benzyl hexadecyloxypropyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]thymine 155 uracil-1-ylhexadecyloxypropyl benzyl benzyl hexadecyloxypropyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]uracil 156 2,6- hexadecyloxypropylbenzyl benzyl hexadecyloxypropyl 9-(S)-[(3- diaminopurin- methoxy-2-9-yl phosphonomethoxy)propyl]2,6- diaminopurine 157 guanin-9-yl1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]guanine158 adenine-9-yl 1-O-octadecyl-2-O- benzyl benzyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]adenine 159 cytosine-1-yl1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]cytosine160 thymin-1-yl 1-O-octadecyl-2-O- benzyl benzyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]thymine 161 uracil-1-yl1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]uracil162 2,6- 1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-sndiaminopurin- benzyl-sn glyceryl glyceryl 9-(S)-[(3-methoxy-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 163 guanin-9-yloctadecyloxyethyl phenyl phenyl octadecyloxyethyl 9-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]guanine 164 adenine-9-yl octadecyloxyethylphenyl phenyl octadecyloxyethyl 9-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]adenine 165 cytosine-1-yl octadecyloxyethylphenyl phenyl octadecyloxyethyl 1-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]cytosine 166 thymin-1-yl octadecyloxyethylphenyl phenyl octadecyloxyethyl 1-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]thymine 167 uracil-1-yl octadecyloxyethyl phenylphenyl octadecyloxyethyl 1-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]uracil 168 2,6- octadecyloxyethyl phenyl phenyloctadecyloxyethyl 9-(S)-[(3- diaminopurin- methoxy-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 169 guanin-9-ylhexadecyloxypropyl phenyl phenyl hexadecyloxypropyl 9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]guanine 170 adenine-9-ylhexadecyloxypropyl phenyl phenyl hexadecyloxypropyl 9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]adenine 171 cytosine-1-ylhexadecyloxypropyl phenyl phenyl hexadecyloxypropyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]cytosine 172 thymin-1-ylhexadecyloxypropyl phenyl phenyl hexadecyloxypropyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]thymine 173 uracil-1-ylhexadecyloxypropyl phenyl phenyl hexadecyloxypropyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]uracil 174 2,6- hexadecyloxypropylphenyl phenyl hexadecyloxypropyl 9-(S)-[(3- diaminopurin- methoxy-2-9-yl phosphonomethoxy)propyl]2,6- diaminopurine 175 guanin-9-yl1-O-octadecyl-2-O- phenyl phenyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]guanine176 adenine-9-yl 1-O-octadecyl-2-O- phenyl phenyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]adenine 177 cytosine-1-yl1-O-octadecyl-2-O- phenyl phenyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]cytosine178 thymin-1-yl 1-O-octadecyl-2-O- phenyl phenyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]thymine 179 uracil-1-yl1-O-octadecyl-2-O- phenyl phenyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]uracil180 2,6- 1-O-octadecyl-2-O- phenyl phenyl 1-O-octadecyl-2-O-benzyl-sndiaminopurin- benzyl-sn glyceryl glyceryl 9-(S)-[(3-methoxy-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 181 guanin-9-yloctadecyloxyethyl ethyl ethyl octadecyloxyethyl 9-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]guanine 182 adenine-9-yl octadecyloxyethyl ethylethyl octadecyloxyethyl 9-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]adenine 183 cytosine-1-yl octadecyloxyethylethyl ethyl octadecyloxyethyl 1-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]cytosine 184 thymin-1-yl octadecyloxyethyl ethylethyl octadecyloxyethyl 1-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]thymine 185 uracil-1-yl octadecyloxyethyl ethylethyl octadecyloxyethyl 1-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]uracil 186 2,6- octadecyloxyethyl ethyl ethyloctadecyloxyethyl 9-(S)-[(3- diaminopurin- methoxy-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 187 guanin-9-ylhexadecyloxypropyl ethyl ethyl hexadecyloxypropyl 9-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]guanine 188 adenine-9-yl hexadecyloxypropylethyl ethyl hexadecyloxypropyl 9-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]adenine 189 cytosine-1-yl hexadecyloxypropylethyl ethyl hexadecyloxypropyl 1-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]cytosine 190 thymin-1-yl hexadecyloxypropylethyl ethyl hexadecyloxypropyl 1-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]thymine 191 uracil-1-yl hexadecyloxypropyl ethylethyl hexadecyloxypropyl 1-(S)-[(3- methoxy-2-phosphonomethoxy)propyl]uracil 192 2,6- hexadecyloxypropyl ethyl ethylhexadecyloxypropyl 9-(S)-[(3- diaminopurin- methoxy-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 193 guanin-9-yl1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]guanine194 adenine-9-yl 1-O-octadecyl-2-O- ethyl ethyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]adenine 195 cytosine-1-yl1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]cytosine196 thymin-1-yl 1-O-octadecyl-2-O- ethyl ethyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]thymine 197 uracil-1-yl1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]uracil198 2,6- 1-O-octadecyl-2-O- ethyl phenyl 1-O-octadecyl-2-O-benzyl-sndiaminopurin- benzyl-sn glyceryl glycerl 9-(S)-[(3-methoxy-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 199 guanin-9-yloctadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]guanine 200 adenine-9-yloctadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]adenine 201 cytosine-1-octadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]cytosine 202 thymin-1-yloctadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]thymine 203 uracil-1-yloctadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]uracil 204 2,6- octadecyloxyethylgalactosyl galactosyl octadecyloxyethyl 9-(S)-[(3- diaminopurin-methoxy-2- 9-yl phosphonomethoxy)propyl]2,6- diaminopurine 205guanin-9-yl hexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl9-(S)- [(3-methoxy-2- phosphonomethoxy)propyl]guanine 206 adenine-9-ylhexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl 9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]adenine 207 cytosine-1-ylhexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]cytosine 208 thymin-1-ylhexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]thymine 209 uracil-1-ylhexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]uracil 210 2,6-hexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl 9-(S)-diaminopurin- [(3-methoxy-2- 9-yl phosphonomethoxy)propyl]2,6-diaminopurine 211 guanin-9-yl 1-O-octadecyl-2-O- galactosyl galactosyl1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl sn glyceryl9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]guanine 212 adenine-9-yl1-O-octadecyl-2-O- galactosyl galactosyl 1-O-octadecyl-2-O-benzyl-benzyl-sn glyceryl sn glyceryl 9-(S)-[(3-methoxy-2-phosphonomethoxy)propyl]adenine 213 cytosine-1-yl 1-O-octadecyl-2-O-galactosyl galactosyl 1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl snglyceryl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]cytosine 214thymin-1-yl 1-O-octadecyl-2-O- galactosyl galactosyl1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl sn glyceryl1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]thymine 215 uracil-1-yl1-O-octadecyl-2-O- galactosyl galactosyl 1-O-octadecyl-2-O-benzyl-benzyl-sn glyceryl sn glyceryl 1-(S)-[(3-methoxy-2-phosphonomethoxy)propyl]uracil 216 2,6- 1-O-octadecyl-2-O- galactosylgalactosyl 1-O-octadecyl-2-O-benzyl- diaminopurin- benzyl-sn glyceryl snglyceryl 9-(S)-[(3-methoxy-2- 9-yl phosphonomethoxy)propyl]2,6-diaminopurine

TABLE 4 (S)-3-hydroxy-2-phosphonomethoxypropyl [(S)-HPMP] diestercompounds

Cmpd No. B_(Nuc)/B_(Nuc(a)) L/L^(a) R/R^(a) Name 217 guanin-9-yloctadecyloxyethyl benzyl benzyl octadecyloxyethyl 9-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]guanine 218 adenine-9-yl octadecyloxyethylbenzyl benzyl octadecyloxyethyl 9-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]adenine 219 cytosine-1-yl octadecyloxyethylbenzyl benzyl octadecyloxyethyl 1-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]cytosine 220 thymin-1-yl octadecyloxyethylbenzyl benzyl octadecyloxyethyl 1-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]thymine 221 uracil-1-yl octadecyloxyethyl benzylbenzyl octadecyloxyethyl 1-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]uracil 222 2,6- octadecyloxyethyl benzyl benzyloctadecyloxyethyl 9-(S)-[(3- diaminopurin- hydroxy-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 223 guanin-9-ylhexadecyloxypropyl benzyl benzyl hexadecyloxypropyl 9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]guanine 224 adenine-9-ylhexadecyloxypropyl benzyl benzyl hexadecyloxypropyl 9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]adenine 225 cytosine-1-ylhexadecyloxypropyl benzyl benzyl hexadecyloxypropyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]cytosine 226 thymin-1-ylhexadecyloxypropyl benzyl benzyl hexadecyloxypropyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]thymine 227 uracil-1-ylhexadecyloxypropyl benzyl benzyl hexadecyloxypropyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]uracil 228 2,6- hexadecyloxypropylbenzyl benzyl hexadecyloxypropyl 9-(S)-[(3- diaminopurin- hydroxy-2-9-yl phosphonomethoxy)propyl]2,6- diaminopurine 229 guanin-9-yl1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]guanine230 adenine-9-yl 1-O-octadecyl-2-O- benzyl benzyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]adenine 231 cytosine-1-yl1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]cytosine232 thymin-1-yl 1-O-octadecyl-2-O- benzyl benzyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]thymine 233 uracil-1-yl1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]uracil234 2,6- 1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-sndiaminopurin- benzyl-sn glyceryl glyceryl 9-(S)-[(3-hydroxy-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 235 guanin-9-yloctadecyloxyethyl phenyl phenyl octadecyloxyethyl 9-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]guanine 236 adenine-9-yl octadecyloxyethylphenyl phenyl octadecyloxyethyl 9-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]adenine 237 cytosine-1-yl octadecyloxyethylphenyl phenyl octadecyloxyethyl 1-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]cytosine 238 thymin-1-yl octadecyloxyethylphenyl phenyl octadecyloxyethyl 1-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]thymine 239 uracil-1-yl octadecyloxyethyl phenylphenyl octadecyloxyethyl 1-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]uracil 240 2,6- octadecyloxyethyl phenyl phenyloctadecyloxyethyl 9-(S)-[(3- diaminopurin- hydroxy-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 241 guanin-9-ylhexadecyloxypropyl phenyl phenyl hexadecyloxypropyl 9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]guanine 242 adenine-9-ylhexadecyloxypropyl phenyl phenyl hexadecyloxypropyl 9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]adenine 243 cytosine-1-ylhexadecyloxypropyl phenyl phenyl hexadecyloxypropyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]cytosine 244 thymin-1-ylhexadecyloxypropyl phenyl phenyl hexadecyloxypropyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]thymine 245 uracil-1-ylhexadecyloxypropyl phenyl phenyl hexadecyloxypropyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]uracil 246 2,6- hexadecyloxypropylphenyl phenyl hexadecyloxypropyl 9-(S)-[(3- diaminopurin- hydroxy-2-9-yl phosphonomethoxy)propyl]2,6- diaminopurine 247 guanin-9-yl1-O-octadecyl-2-O- phenyl phenyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]guanine248 adenine-9-yl 1-O-octadecyl-2-O- phenyl phenyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]adenine 249 cytosine-1-yl1-O-octadecyl-2-O- phenyl phenyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]cytosine250 thymin-1-yl 1-O-octadecyl-2-O- phenyl phenyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]thymine 251 uracil-1-yl1-O-octadecyl-2-O- phenyl phenyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]uracil252 2,6- 1-O-octadecyl-2-O- phenyl phenyl 1-O-octadecyl-2-O-benzyl-sndiaminopurin- benzyl-sn glyceryl glyceryl 9-(S)-[(3-hydroxy-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 253 guanin-9-yloctadecyloxyethyl ethyl ethyl octadecyloxyethyl 9-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]guanine 254 adenine-9-yl octadecyloxyethyl ethylethyl octadecyloxyethyl 9-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]adenine 255 cytosine-1-yl octadecyloxyethylethyl ethyl octadecyloxyethyl 1-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]cytosine 256 thymin-1-yl octadecyloxyethyl ethylethyl octadecyloxyethyl 1-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]thymine 257 uracil-1-yl octadecyloxyethyl ethylethyl octadecyloxyethyl 1-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]uracil 258 2,6- octadecyloxyethyl ethyl ethyloctadecyloxyethyl 9-(S)-[(3- diaminopurin- hydroxy-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 259 guanin-9-ylhexadecyloxypropyl ethyl ethyl hexadecyloxypropyl 9-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]guanine 260 adenine-9-yl hexadecyloxypropylethyl ethyl hexadecyloxypropyl 9-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]adenine 261 cytosine-1-yl hexadecyloxypropylethyl ethyl hexadecyloxypropyl 1-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]cytosine 262 thymin-1-yl hexadecyloxypropylethyl ethyl hexadecyloxypropyl 1-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]thymine 263 uracil-1-yl hexadecyloxypropyl ethylethyl hexadecyloxypropyl 1-(S)-[(3- hydroxy-2-phosphonomethoxy)propyl]uracil 264 2,6- hexadecyloxypropyl ethyl ethylhexadecyloxypropyl 9-(S)-[(3- diaminopurin- hydroxy-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 265 guanin-9-yl1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]guanine266 adenine-9-yl 1-O-octadecyl-2-O- ethyl ethyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]adenine 267 cytosine-1-yl1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]cytosine268 thymin-1-yl 1-O-octadecyl-2-O- ethyl ethyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]thymine 269 uracil-1-yl1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]uracil270 2,6- 1-O-octadecyl-2-O- ethyl phenyl 1-O-octadecyl-2-O-benzyl-sndiaminopurin- benzyl-sn glyceryl glyceryl 9-(S)-[(3-hydroxy-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 271 guanin-9-yloctadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]guanine 272 adenine-9-yloctadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]adenine 273 cytosine-1-yloctadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 1-(S)-[(3-hydrox-2- phosphonomethoxy)propyl]cytosine 274 thymin-1-yloctadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]thymine 275 uracil-1-yloctadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]uracil 276 2,6- octadecyloxyethylgalactosyl galactosyl octadecyloxyethyl 9-(S)-[(3- diaminopurin-hydroxy-2- 9-yl phosphonomethoxy)propyl]2,6- diaminopurine 277guanin-9-yl hexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl9-(S)- [(3-hydroxy-2- phosphonomethoxy)propyl]guanine 278 adenine-9-ylhexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl 9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]adenine 279 cytosine-1-ylhexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]cytosine 280 thymin-1-ylhexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]thymine 281 uracil-1-ylhexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]uracil 282 2,6-hexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl 9-(S)-diaminopurin- [(3-hydroxy-2- 9-yl phosphonomethoxy)propyl]2,6-diaminopurine 283 guanin-9-yl 1-O-octadecyl-2-O- galactosyl galactosyl1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl sn glyceryl9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]guanine 284 adenine-9-yl1-O-octadecyl-2-O- galactosyl galactosyl 1-O-octadecyl-2-O-benzyl-benzyl-sn glyceryl sn glyceryl 9-(S)-[(3-hydroxy-2-phosphonomethoxy)propyl]adenine 285 cytosine-1-yl 1-O-octadecyl-2-O-galactosyl galactosyl 1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl snglyceryl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]cytosine 286thymin-1-yl 1-O-octadecyl-2-O- galactosyl galactosyl1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl sn glyceryl1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]thymine 287 uracil-1-yl1-O-octadecyl-2-O- galactosyl galactosyl 1-O-octadecyl-2-O-benzyl-benzyl-sn glyceryl sn glyceryl 1-(S)-[(3-hydroxy-2-phosphonomethoxy)propyl]uracil 288 2,6- 1-O-octadecyl-2-O- galactosylgalactosyl 1-O-octadecyl-2-O-benzyl- diaminopurin- benzyl-sn glyceryl snglyceryl 9-(S)-[(3-hydroxy-2- 9-yl phosphonomethoxy)propyl]2,6-diaminopurine

TABLE 5 (S)-3-fluoro-2-phosphonomethoxypropyl [(S)-FPMP] diestercompounds

Cmpd No. B_(Nuc)/B_(Nuc(a)) L/L^(a) R/R^(a) Name 289 guanin-9-yloctadecyloxyethyl benzyl benzyl octadecyloxyethyl 9-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]guanine 290 adenine-9-yl octadecyloxyethylbenzyl benzyl octadecyloxyethyl 9-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]adenine 291 cytosine-1-yl octadecyloxyethylbenzyl benzyl octadecyloxyethyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]cytosine 292 thymin-1-yl octadecyloxyethylbenzyl benzyl octadecyloxyethyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]thymine 293 uracil-1-yl octadecyloxyethyl benzylbenzyl octadecyloxyethyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]uracil 294 2,6- octadecyloxyethyl benzyl benzyloctadecyloxyethyl 9-(S)-[(3- diaminopurin- fluoro-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 295 guanin-9-ylhexadecyloxypropyl benzyl benzyl hexadecyloxypropyl 9-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]guanine 296 adenine-9-yl hexadecyloxypropylbenzyl benzyl hexadecyloxypropyl 9-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]adenine 297 cytosine-1-yl hexadecyloxypropylbenzyl benzyl hexadecyloxypropyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]cytosine 298 thymin-1-yl hexadecyloxypropylbenzyl benzyl hexadecyloxypropyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]thymine 299 uracil-1-yl hexadecyloxypropylbenzyl benzyl hexadecyloxypropyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]uracil 300 2,6- hexadecyloxypropyl benzyl benzylhexadecyloxypropyl 9-(S)-[(3- diaminopurin- fluoro-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 301 guanin-9-yl1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 9-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]guanine302 adenine-9-yl 1-O-octadecyl-2-O- benzyl benzyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl9-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]adenine 303 cytosine-1-yl1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]cytosine304 thymin-1-yl 1-O-octadecyl-2-O- benzyl benzyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]thymine 305 uracil-1-yl1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]uracil 3062,6- 1-O-octadecyl-2-O- benzyl benzyl 1-O-octadecyl-2-O-benzyl-sndiaminopurin- benzyl-sn glyceryl glyceryl 9-(S)-[(3-fluoro-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 307 guanin-9-yloctadecyloxyethyl phenyl phenyl octadecyloxyethyl 9-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]guanine 308 adenine-9-yl octadecyloxyethylphenyl phenyl octadecyloxyethyl 9-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]adenine 309 cytosine-1-yl octadecyloxyethylphenyl phenyl octadecyloxyethyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]cytosine 310 thymin-1-yl octadecyloxyethylphenyl phenyl octadecyloxyethyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]thymine 311 uracil-1-yl octadecyloxyethyl phenylphenyl octadecyloxyethyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]uracil 312 2,6- octadecyloxyethyl phenyl phenyloctadecyloxyethyl 9-(S)-[(3- diaminopurin- fluoro-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 313 guanin-9-ylhexadecyloxypropyl phenyl phenyl hexadecyloxypropyl 9-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]guanine 314 adenine-9-yl hexadecyloxypropylphenyl phenyl hexadecyloxypropyl 9-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]adenine 315 cytosine-1-yl hexadecyloxypropylphenyl phenyl hexadecyloxypropyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]cytosine 316 thymin-1-yl hexadecyloxypropylphenyl phenyl hexadecyloxypropyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]thymine 317 uracil-1-yl hexadecyloxypropylphenyl phenyl hexadecyloxypropyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]uracil 318 2,6- hexadecyloxypropyl phenyl phenylhexadecyloxypropyl 9-(S)-[(3- diaminopurin- fluoro-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 319 guanin-9-yl1-O-octadecyl-2-O- phenyl phenyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 9-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]guanine320 adenine-9-yl 1-O-octadecyl-2-O- phenyl phenyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl9-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]adenine 321 cytosine-1-yl1-O-octadecyl-2-O- phenyl phenyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]cytosine322 thymin-1-yl 1-O-octadecyl-2-O- phenyl phenyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]thymine 323 uracil-1-yl1-O-octadecyl-2-O- phenyl phenyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]uracil 3242,6- 1-O-octadecyl-2-O- phenyl phenyl 1-O-octadecyl-2-O-benzyl-sndiaminopurin- benzyl-sn glyceryl glyceryl 9-(S)-[(3-fluoro-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 325 guanin-9-yloctadecyloxyethyl ethyl ethyl octadecyloxyethyl 9-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]guanine 326 adenine-9-yl octadecyloxyethyl ethylethyl octadecyloxyethyl 9-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]adenine 327 cytosine-1-yl octadecyloxyethylethyl ethyl octadecyloxyethyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]cytosine 328 thymin-1-yl octadecyloxyethyl ethylethyl octadecyloxyethyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]thymine 329 uracil-1-yl octadecyloxyethyl ethylethyl octadecyloxyethyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]uracil 330 2,6- octadecyloxyethyl ethyl ethyloctadecyloxyethyl 9-(S)-[(3- diaminopurin- fluoro-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 331 guanin-9-ylhexadecyloxypropyl ethyl ethyl hexadecyloxypropyl 9-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]guanine 332 adenine-9-yl hexadecyloxypropylethyl ethyl hexadecyloxypropyl 9-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]adenine 333 cytosine-1-yl hexadecyloxypropylethyl ethyl hexadecyloxypropyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]cytosine 334 thymin-1-yl hexadecyloxypropylethyl ethyl hexadecyloxypropyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]thymine 335 uracil-1-yl hexadecyloxypropyl ethylethyl hexadecyloxypropyl 1-(S)-[(3- fluoro-2-phosphonomethoxy)propyl]uracil 336 2,6- hexadecyloxypropyl ethyl ethylhexadecyloxypropyl 9-(S)-[(3- diaminopurin- fluoro-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 337 guanin-9-yl1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 9-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]guanine338 adenine-9-yl 1-O-octadecyl-2-O- ethyl ethyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl9-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]adenine 339 cytosine-1-yl1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]cytosine340 thymin-1-yl 1-O-octadecyl-2-O- ethyl ethyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]thymine 341 uracil-1-yl1-O-octadecyl-2-O- ethyl ethyl 1-O-octadecyl-2-O-benzyl-sn benzyl-snglyceryl glyceryl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]uracil 3422,6- 1-O-octadecyl-2-O- ethyl phenyl 1-O-octadecyl-2-O-benzyl-sndiaminopurin- benzyl-sn glyceryl glyceryl 9-(S)-[(3-fluoro-2- 9-ylphosphonomethoxy)propyl]2,6- diaminopurine 343 guanin-9-yloctadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 9-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]guanine 344 adenine-9-yloctadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 9-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]adenine 345 cytosine-1-yloctadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]cytosine 346 thymin-1-yloctadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]thymine 347 uracil-1-yloctadecyloxyethyl galactosyl galactosyl octadecyloxyethyl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]uracil 348 2,6- octadecyloxyethylgalactosyl galactosyl octadecyloxyethyl 9-(S)-[(3- diaminopurin-fluoro-2- 9-yl phosphonomethoxy)propyl]2,6- diaminopurine 349guanin-9-yl hexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl9-(S)-[(3- fluoro-2- phosphonomethoxy)propyl]guanine 350 adenine-9-ylhexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl 9-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]adenine 351 cytosine-1-ylhexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]cytosine 352 thymin-1-ylhexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]thymine 353 uracil-1-ylhexadecyloxypropyl galactosyl galactosyl hexadecyloxypropyl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]uracil 354 2,6- hexadecyloxypropylgalactosyl galactosyl hexadecyloxypropyl 9-(S)- diaminopurin-[(3-fluoro-2- 9-yl phosphonomethoxy)propyl]2,6- diaminopurine 355guanin-9-yl 1-O-octadecyl-2-O- galactosyl galactosyl1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl sn glyceryl9-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]guanine 356 adenine-9-yl1-O-octadecyl-2-O- galactosyl galactosyl 1-O-octadecyl-2-O-benzyl-benzyl-sn glyceryl sn glyceryl 9-(S)-[(3-fluoro-2-phosphonomethoxy)propyl]adenine 357 cytosine-1-yl 1-O-octadecyl-2-O-galactosyl galactosyl 1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl snglyceryl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]cytosine 358thymin-1-yl 1-O-octadecyl-2-O- galactosyl galactosyl1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl sn glyceryl1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]thymine 359 uracil-1-yl1-O-octadecyl-2-O- galactosyl galactosyl 1-O-octadecyl-2-O-benzyl-benzyl-sn glyceryl sn glyceryl 1-(S)-[(3-fluoro-2-phosphonomethoxy)propyl]uracil 360 2,6- 1-O-octadecyl-2-O- galactosylgalactosyl 1-O-octadecyl-2-O-benzyl- diaminopurin- benzyl-sn glyceryl snglyceryl 9-(S)-[(3-fluoro-2- 9-yl phosphonomethoxy)propyl]2,6-diaminopurine

TABLE 6 Phosphonomethoxyethyl (PME) diester compounds

Cmpd No. B_(Nuc)/B_(Nuc(a)) L/L^(a) R/R^(a) Name 361 guanin-9-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 9-(2-phosphonomethoxyethyl)guanine 362 adenine-9-yl octadecyloxyethylnaphthyl naphthyl octadecyloxyethyl 9-(2- phosphonomethoxyethyl)adenine363 cytosine-1-yl octadecyloxyethyl naphthyl naphthyl octadecyloxyethyl1-(2- phosphonomethoxyethyl)cytosine 364 thymin-1-yl octadecyloxyethylnaphthyl naphthyl octadecyloxyethyl 1-(2- phosphonomethoxyethyl)thymine365 uracil-1-yl octadecyloxyethyl naphthyl naphthyl octadecyloxyethyl9-(2- phosphonomethoxyethyl)uracil 366 2,6- octadecyloxyethyl naphthylnaphthyl octadecyloxyethyl 9-(2- diaminopurin-phosphonomethoxyethyl)-2,6- 9-yl diaminopurine 367 guanin-9-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 9-(2-phosphonomethoxyethyl)guanine 368 adenine-9-yl hexadecyloxypropylnaphthyl naphthyl hexadecyloxypropyl 9-(2- phosphonomethoxyethyl)adenine369 cytosine-1-yl hexadecyloxypropyl naphthyl naphthylhexadecyloxypropyl 1-(2- phosphonomethoxyethyl)cytosine 370 thymin-1-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 1-(2-phosphonomethoxyethyl)thymine 371 uracil-1-yl hexadecyloxypropylnaphthyl naphthyl hexadecyloxypropyl 9-(2- phosphonomethoxyethyl)uracil372 2,6- hexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 9-(2-diaminopurin- phosphonomethoxyethyl)-2,6- 9-yl diaminopurine 373guanin-9-yl 1-O-octadecyl-2-O- naphthyl naphthyl1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl sn glyceryl 9-(2-phosphonomethoxyethyl)guanine 374 adenine-9-yl 1-O-octadecyl-2-O-naphthyl naphthyl 1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl snglyceryl 9-(2- phosphonomethoxyethyl)adenine 375 cytosine-1-yl1-O-octadecyl-2-O- naphthyl naphthyl 1-O-octadecyl-2-O-benzyl- benzyl-snglyceryl sn glyceryl 1-(2- phosphonomethoxyethyl)cytosine 376thymin-1-yl 1-O-octadecyl-2-O- naphthyl naphthyl1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl sn glyceryl1-(2-phosphonomethoxy- ethyl)thymine 377 uracil-1-yl 1-O-octadecyl-2-O-naphthyl naphthyl 1-O-octadecyl-2-O-benzyl- benzyl-sn glyceryl snglyceryl 9-(2-phosphonomethoxy- ethyl)uracil 378 2,6- 1-O-octadecyl-2-O-naphthyl naphthyl 1-O-octadecyl-2-O-benzyl- diaminopurin- benzyl-snglyceryl sn glyceryl 9-(2-phosphonomethoxy- 9-ylethyl)-2,6-diaminopurine

TABLE 7 (R)-phosphonomethoxypropyl [(R)-PMP] diester compounds

Cmpd No. B_(Nuc)/B_(Nuc(a)) L/L^(a) R/R^(a) Name 379 guanin-9-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 9-(R)-[(2-phosphonomethoxy)propyl]guanine 380 adenine-9-yl octadecyloxyethylnaphthyl naphthyl octadecyloxyethyl 9-(R)-[(2-phosphonomethoxy)propyl]adenine 381 cytosine-1-yl octadecyloxyethylnaphthyl naphthyl octadecyloxyethyl 1-(R)-[(2-phosphonomethoxy)propyl]cytosine 382 thymin-1-yl octadecyloxyethylnaphthyl naphthyl octadecyloxyethyl 1-(R)-[(2-phosphonomethoxy)propyl]thymine 383 uracil-1-yl octadecyloxyethylnaphthyl naphthyl octadecyloxyethyl 1-(R)-[(2-phosphonomethoxy)propyl]uracil 384 2,6- octadecyloxyethyl naphthylnaphthyl octadecyloxyethyl 9-(R)-[(2- diaminopurin-phosphonomethoxy)propyl]-2,6- 9-yl diaminopurine 385 guanin-9-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 9-(R)-[(2-phosphonomethoxy)propyl]guanine 386 adenine-9-yl hexadecyloxypropylnaphthyl naphthyl hexadecyloxypropyl 9-(R)-[(2-phosphonomethoxy)propyl]adenine 387 cytosine-1-yl hexadecyloxypropylnaphthyl naphthyl hexadecyloxypropyl 1-(R)- [(2-phosphonomethoxy)propyl]cytosine 388 thymin-1-yl hexadecyloxypropylnaphthyl naphthyl hexadecyloxypropyl 1-(R)- [(2-phosphonomethoxy)propyl]thymine 389 uracil-1-yl hexadecyloxypropylnaphthyl naphthyl hexadecyloxypropyl 1-(R)-[(2phosphonomethoxy)propyl]uracil 390 2,6- hexadecyloxypropyl naphthylnaphthyl hexadecyloxypropyl 9-(R)- diaminopurin-[(2-phosphonomethoxy)propyl]-2,6- 9-yl diaminopurine 391 guanin-9-yl1-O-octadecyl-2-O- naphthyl naphthyl 1-O-octadecyl-2-O-benzyl-snbenzyl-sn glyceryl glyceryl 9-(R)-[(2- phosphonomethoxy)propyl]guanine392 adenine-9-yl 1-O-octadecyl-2-O- naphthyl naphthyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl 9-(R)-[(2-phosphonomethoxy)propyl]adenine 393 cytosine-1-yl 1-O-octadecyl-2-O-naphthyl naphthyl 1-O-octadecyl-2-O-benzyl-sn benzyl-sn glycerylglyceryl 1-(R)-[(2- phosphonomethoxy)propyl]cytosine 394 thymin-1-yl1-O-octadecyl-2-O- naphthyl naphthyl 1-O-octadecyl-2-O-benzyl-snbenzyl-sn glyceryl glyceryl 1-(R)-[(2- phosphonomethoxy)propyl]thymine395 uracil-1-yl 1-O-octadecyl-2-O- naphthyl naphthyl1-O-octatlecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl 9-(R)-[(2-phosphonomethoxy)propyl]uracil 396 2,6- 1-O-octadecyl-2-O- naphthylnaphthyl 1-O-octadecyl-2-O-benzyl-sn diaminopurin- benzyl-sn glycerylglyceryl 9-(R)-[(2- 9-yl phosphonomethoxy)propyl]-2,6- diaminopurine

TABLE 8 (S)-3-methoxy-2-phosphonomethoxypropyl [(S)-MPMP] diestercompounds

Cmpd No. B_(Nuc)/B_(Nuc(a)) L/L^(a) R/R^(a) Name 397 guanin-9-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]guanine 398 adenine-9-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]adenine 399 cytosine-1-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]cytosine 400 thymin-1-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]thymine 401 uracil-1-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]uracil 402 2,6- octadecyloxyethylnaphthyl naphthyl octadecyloxyethyl 9-(S)-[(3- diaminopurin- methoxy-2-9-yl phosphonomethoxy)propyl]-2,6- diaminopurine 403 guanin-9-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]guanine 404 adenine-9-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]adenine 405 cytosine-1-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]cytosine 406 thymin-1-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]thymine 407 uracil-1-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]uracil 408 2,6- hexadecyloxypropylnaphthyl naphthyl hexadecyloxypropyl 9-(S)-[(3- diaminopurin- methoxy-2-9-yl phosphonomethoxy)propyl]-2,6- diaminopurine 409 guanin-9-yl1-O-octadecyl-2-O- naphthyl naphthyl 1-O-octadecyl-2-O-benzyl-snbenzyl-sn glyceryl glyceryl 9-(S)-[(3-methoxy-2-phosphonomethoxy)propyl]guanine 410 adenine-9-yl 1-O-octadecyl-2-O-naphthyl naphthyl 1-O-octadecyl-2-O-benzyl-sn benzyl-sn glycerylglyceryl 9-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]adenine 411cytosine-1-yl 1-O-octadecyl-2-O- naphthyl naphthyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]cytosine 412 thymin-1-yl1-O-octadecyl-2-O- naphthyl naphthyl 1-O-octadecyl-2-O-benzyl-snbenzyl-sn glyceryl glyceryl 1-(S)-[(3-methoxy-2-phosphonomethoxy)propyl]thymine 413 uracil-1-yl 1-O-octadecyl-2-O-naphthyl naphthyl 1-O-octatlecyl-2-O-benzyl-sn benzyl-sn glycerylglyceryl 1-(S)-[(3-methoxy-2- phosphonomethoxy)propyl]uracil 414 2,6-1-O-octadecyl-2-O- naphthyl naphthyl 1-O-octadecyl-2-O-benzyl-sndiaminopurin- benzyl-sn glyceryl glyceryl 9-(S)-[(3-methoxy-2- 9-ylphosphonomethoxy)propyl]-2,6- diaminopurine

TABLE 9 (S)-3-hydroxy-2-phosphonomethoxypropyl [(S)-HPMP] diestercompounds

Cmpd No. B_(Nuc)/B_(Nuc(a)) L/L^(a) R/R^(a) Name 415 guanin-9-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]guanine 416 adenine-9-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]adenine 417 cytosine-1-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]cytosine 418 thymin-1-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]thymine 419 uracil-1-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]uracil 420 2,6- octadecyloxyethylnaphthyl naphthyl octadecyloxyethyl 9-(S)-[(3- diaminopurin- hydroxy-2-9-yl phosphonomethoxy)propyl]-2,6- diaminopurine 421 guanin-9-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]guanine 422 adenine-9-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]adenine 423 cytosine-1-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]cytosine 424 thymin-1-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]thymine 425 uracil-1-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]uracil 426 2,6- hexadecyloxypropylnaphthyl naphthyl hexadecyloxypropyl 9-(S)-[(3- diaminopurin- hydroxy-2-9-yl phosphonomethoxy)propyl]-2,6- diaminopurine 427 guanin-9-yl1-O-octadecyl-2-O- naphthyl naphthyl 1-O-octadecyl-2-O-benzyl-snbenzyl-sn glyceryl glyceryl 9-(S)-[(3-hydroxy-2-phosphonomethoxy)propyl]guanine 428 adenine-9-yl 1-O-octadecyl-2-O-naphthyl naphthyl 1-O-octadecyl-2-O-benzyl-sn benzyl-sn glycerylglyceryl 9-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]adenine 429cytosine-1-yl 1-O-octadecyl-2-O- naphthyl naphthyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]cytosine 430 thymin-1-yl1-O-octadecyl-2-O- naphthyl naphthyl 1-O-octadecyl-2-O-benzyl-snbenzyl-sn glyceryl glyceryl 1-(S)-[(3-hydroxy-2-phosphonomethoxy)propyl]thymine 431 uracil-1-yl 1-O-octadecyl-2-O-naphthyl naphthyl 1-O-octatlecyl-2-O-benzyl-sn benzyl-sn glycerylglyceryl 1-(S)-[(3-hydroxy-2- phosphonomethoxy)propyl]uracil 432 2,6-1-O-octadecyl-2-O- naphthyl naphthyl 1-O-octadecyl-2-O-benzyl-sndiaminopurin- benzyl-sn glyceryl glyceryl 9-(S)-[(3-hydroxy-2- 9-ylphosphonomethoxy)propyl]-2,6- diaminopurine

TABLE 10 (S)-3-fluoro-2-phosphonomethoxypropyl [(S)-FPMP] diestercompounds

Cmpd No. B_(Nuc)/B_(Nuc(a)) L/L^(a) R/R^(a) Name 433 guanin-9-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 9-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]guanine 434 adenine-9-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 9-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]adenine 435 cytosine-1-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]cytosine 436 thymin-1-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]thymine 437 uracil-1-yloctadecyloxyethyl naphthyl naphthyl octadecyloxyethyl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]uracil 438 2,6- octadecyloxyethylnaphthyl naphthyl octadecyloxyethyl 9-(S)-[(3- diaminopurin- fluoro-2-9-yl phosphonomethoxy)propyl]-2,6- diaminopurine 439 guanin-9-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 9-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]guanine 440 adenine-9-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 9-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]adenine 441 cytosine-1-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]cytosine 442 thymin-1-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]thymine 443 uracil-1-ylhexadecyloxypropyl naphthyl naphthyl hexadecyloxypropyl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]uracil 444 2,6- hexadecyloxypropylnaphthyl naphthyl hexadecyloxypropyl 9-(S)-[(3- diaminopurin- fluoro-2-9-yl phosphonomethoxy)propyl]-2,6- diaminopurine 445 guanin-9-yl1-O-octadecyl-2-O- naphthyl naphthyl 1-O-octadecyl-2-O-benzyl-snbenzyl-sn glyceryl glyceryl 9-(S)-[(3-fluoro-2-phosphonomethoxy)propyl]guanine 446 adenine-9-yl 1-O-octadecyl-2-O-naphthyl naphthyl 1-O-octadecyl-2-O-benzyl-sn benzyl-sn glycerylglyceryl 9-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]adenine 447cytosine-1-yl 1-O-octadecyl-2-O- naphthyl naphthyl1-O-octadecyl-2-O-benzyl-sn benzyl-sn glyceryl glyceryl1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]cytosine 448 thymin-1-yl1-O-octadecyl-2-O- naphthyl naphthyl 1-O-octadecyl-2-O-benzyl-snbenzyl-sn glyceryl glyceryl 1-(S)-[(3-fluoro-2-phosphonomethoxy)propyl]thymine 449 uracil-1-yl 1-O-octadecyl-2-O-naphthyl naphthyl 1-O-octadecyl-2-O-benzyl-sn benzyl-sn glycerylglyceryl 1-(S)-[(3-fluoro-2- phosphonomethoxy)propyl]uracil 450 2,6-1-O-octadecyl-2-O- naphthyl naphthyl 1-O-octadecyl-2-O-benzyl-sndiaminopurin- benzyl-sn glyceryl glyceryl 9-(S)-[(3-fluoro-2- 9-ylphosphonomethoxy)propyl]-2,6- diaminopurine

Specific compounds contemplated herein include:

Methods of Use

In another aspect, there is provided a method for treating a viraldisease in a subject. The method includes administering to a subject inneed thereof a therapeutically effective amount of a compound withstructure of any of Formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5)and/or (Ia). In embodiments, L/L^(a) of any of Formulae (I), (I-1),(I-2), (I-3), (I-4), (I-5) and/or (Ia) is a lipophilic promoiety.

Exemplary viral diseases include human papilloma virus, HIV, hepatitis Bvirus, hepatitis C virus, variola virus (smallpox), vaccinia virus,adenovirus, cytomegalovirus (CMV), herpes simplex viruses, Epstein Barrvirus, BK virus, JC virus, any double stranded DNA virus, felineleukemia virus, feline immunodeficiency virus, and the like. Atherapeutically effective amount of a compound of Formula (I) can beadministered to a human or mammal in need of treatment of a viraldisease.

In embodiments, the compound is administered by a route (topical,intravitreal, oral, intravenous etc.) which results in delivery of anamount sufficient to inhibit replication of the virus. In embodiments,the compound can be administered topically. For example, the compoundcan be administered topically in the form of a cream, a gel or anointment

In another aspect, there is provided a method for treating a disease ordisorder in a subject in need thereof, the method includingadministering to a subject in need thereof a therapeutically effectiveamount of a compound with structure of any of Formulae (I), (I-1),(I-2), (I-3), (I-4), (I-5) and/or (Ia). Aspects for the treatment ofcancer and other neoplastic disorders contemplated herein are based onthe surprising discovery that compounds of Formulae (I) and/or (Ia) areeffective in killing or inhibiting growth of cells that are transformedby human papillomavirus (HPV), for example cervical cancer cells andcervical intraepithelial neoplasia (CIN) lesions. Accordingly, atherapeutically effective amount of a compound of Formula (I), (I-1),(I-2), (I-3), (I-4), (I-5) and/or (Ia) can be administered by anappropriate route (topical, orally, intravenous etc.) to kill or inhibitgrowth of infected/transformed cells. Cells that are transformed byother types of viruses, such as herpes simplex virus-2 (HSV-2), also maybe treated with a compound of Formula (I), (I-1), (I-2), (I-3), (I-4),(I-5) and/or (Ia).

In another aspect, there is provided a method for treating cancer in asubject. The method includes administering to a subject in need thereofa therapeutically effective amount of a compound with the structure ofany of Formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5) and/or (Ia). Inembodiments, L/L^(a) of any of Formulae (I), (I-1), (I-2), (I-3), (I-4),(I-5) and/or (Ia) is a lipophilic promoiety.

In embodiments, the cancer is leukemia, carcinoma and/or sarcoma, suchas cancer of the brain, breast, cervix, colon, pancreas, head and neck,liver, kidney, lung, non-small cell lung, prostate, melanoma,mesothelioma, ovary, sarcoma, stomach, uterus and/or medulloblastoma.Additional examples include, Hodgkin's Disease, Non-Hodgkin's Lymphoma,multiple myeloma, neuroblastoma, ovarian cancer, rhabdomyosarcoma,primary thrombocytosis, primary macroglobulinemia, primary brain tumors,malignant pancreatic insulanoma, malignant carcinoid, urinary bladdercancer, premalignant skin lesions, testicular cancer, lymphomas, thyroidcancer, neuroblastoma, esophageal cancer, genitourinary tract cancer,malignant hypercalcemia, endometrial cancer, adrenal cortical cancer,and neoplasms of the endocrine and exocrine pancreas. In embodiments,the cancer is liver cancer, colon cancer, breast cancer, melanoma, acutemyelogenous leukemia, chronic myelogenous leukemia, and/ornon-small-cell lung cancer.

In another aspect, there is provided a method for treating aproliferative disorder in a subject. The method includes administeringto a subject in need thereof a therapeutically effective amount of acompound with the structure of any of Formulae (I), (I-1), (I-2), (I-3),(I-4), (I-5) and/or (Ia). The proliferative disorder may be caused bythe human papilloma virus. Exemplary proliferative disorders include,e.g., cervical intraepithelial neoplasia (CIN), vulvar intraepithelialneoplasia (VIN), anal intraepithelial neoplasia (AIN), or penile andvenereal warts. In embodiments, L/L^(a) of any of Formulae (I), (I-1),(I-2), (I-3), (I-4), (I-5) and/or (Ia) is a lipophilic promoiety.

In another aspect, there is provided a method for killing or inhibitingthe growth of a transformed cell. The method includes contacting atransformed cell with a therapeutically effective amount of a compoundof any one of Formulae (I), (I-1), (I-2), (I-3), (I-4), (I-5) and/or(Ia).

In another aspect, there is provided a compound of Formula (Ia) orembodiment thereof, or a pharmaceutically acceptable salt, hydrate,solvate or crystalline form thereof, for use in treating a viral diseasein a subject, wherein the viral disease can be selected from humanpapilloma virus (HPV), HIV, hepatitis B virus, hepatitis C virus,variola virus, vaccinia virus, an adenovirus, a cytomegalovirus, herpessimplex virus 1, herpes simplex virus 2, Epstein Barr virus, BK virus,JC virus, feline leukemia virus and feline immunodeficiency virus.

In embodiments, the virus can be human papilloma virus. According to theCDC, HPV is the most common sexually transmitted infection (STI). HPVviruses can be classified into mucosal and cutaneous HPVs. Within eachof these groups, the individual viruses are designated high risk or lowrisk. More than 40 types of HPV's can infect the genital areas of womenand men, and several HPV types can infect the mouth and throat.Additionally, HPV is the most common cause of cervical cancer. Type 16is one of the most prominent strains of HPV and can cause cervicalcancer. Other types of HPVs include, but are not limited to, 2, 3, 4, 5,6, 8, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 63, 66, 68, 69and 82. In embodiments, the use is for treating a plurality of types ofhuman papilloma virus, for example, types described herein. Inembodiments, the use is for more than 2 types of HPV, more than 5 typesof HPV or more than 10 types of HPV. In embodiments, the human papillomavirus can be selected from human papilloma virus type 11, type 16 andtype 18.

In another aspect, there is provided use of a compound of Formula (Ia)or embodiment thereof, or a pharmaceutically acceptable salt, hydrate,solvate or crystalline form thereof, in the preparation of a medicamentfor treating a viral disease in a subject, wherein the viral disease canbe selected from human papilloma virus, HIV, hepatitis B virus,hepatitis C virus, variola virus, vaccinia virus, an adenovirus, acytomegalovirus, herpes simplex virus 1, herpes simplex virus 2, EpsteinBarr virus, BK virus, JC virus, feline leukemia virus and felineimmunodeficiency virus.

In embodiments, the virus can be human papilloma virus. In embodiments,the use is for treating a plurality of types of human papilloma virus,for example, types described herein. In embodiments, the use is for morethan 2 types of HPV, more than 5 types of HPV or more than 10 types ofHPV. In embodiments, the human papilloma virus can be selected fromhuman papilloma virus type 11, type 16 and type 18.

In another aspect, there is provided a method of treating a subjecthaving a viral disease. The method include administering to the subjecthaving a viral disease in need thereof an effective amount of a compoundof Formula (Ia) or embodiment thereof, or a pharmaceutically acceptablesalt, hydrate, solvate or crystalline form thereof, wherein the viraldisease can be selected from human papilloma virus, HIV, hepatitis Bvirus, hepatitis C virus, variola virus, vaccinia virus, an adenovirus,a cytomegalovirus, herpes simplex virus 1, herpes simplex virus 2,Epstein Barr virus, BK virus, JC virus, feline leukemia virus and felineimmunodeficiency virus, thereby treating the viral disease.

In another aspect, there is provided a compound of Formula (Ia) orembodiment thereof, or a pharmaceutically acceptable salt, hydrate,solvate or crystalline form thereof, for use in treating cancer of thecervix in a subject. In some embodiments, the cancer of the cervix canbe caused by a HPV infection, for example, a HPV infection of type 16.

In another aspect, there is provided use of a compound of Formula (Ia)or embodiment thereof, or a pharmaceutically acceptable salt, hydrate,solvate or crystalline form thereof, in the preparation of a medicamentfor treating cancer of the cervix in a subject. In some embodiments, thecancer of the cervix can be caused by a HPV infection, for example, aHPV infection of type 16.

In another aspect, there is provided a method of treating a subjecthaving cancer of the cervix. The method includes administering aneffective amount of a compound of Formula (Ia) or embodiment thereof, ora pharmaceutically acceptable salt, hydrate, solvate or crystalline formthereof, to a subject having cancer of the cervix in need thereof,thereby treating the subject having cancer of the cervix. In someembodiments, the cancer of the cervix can be caused by a HPV infection,for example, a HPV infection of type 16.

In another aspect, there is provided a compound of Formula (Ia) orembodiment thereof, or a pharmaceutically acceptable salt, hydrate,solvate or crystalline form thereof, for use in inhibiting growth of acell transformed by a virus, wherein the virus can be selected fromhuman papilloma virus, HIV, hepatitis B virus, hepatitis C virus,variola virus, vaccinia virus, an adenovirus, a cytomegalovirus, herpessimplex virus 1, herpes simplex virus 2, Epstein Barr virus, BK virus,JC virus, feline leukemia virus and feline immunodeficiency virus.

In another aspect, there is provided use of a compound of Formula (Ia)or embodiment thereof, or a pharmaceutically acceptable salt, hydrate,solvate or crystalline form thereof, in the preparation of a medicamentfor inhibiting growth of a cell transformed by a virus, wherein thevirus can be selected from human papilloma virus, HIV, hepatitis Bvirus, hepatitis C virus, variola virus, vaccinia virus, an adenovirus,a cytomegalovirus, herpes simplex virus 1, herpes simplex virus 2,Epstein Barr virus, BK virus, JC virus, feline leukemia virus and felineimmunodeficiency virus.

In another aspect, there is provided a method of inhibiting growth of acell transformed by a virus. The method includes contacting a compoundof Formula (Ia) or embodiment thereof, or a pharmaceutically acceptablesalt, hydrate, solvate or crystalline form thereof, with a celltransformed by a virus, wherein the virus can be selected from humanpapilloma virus, HIV, hepatitis B virus, hepatitis C virus, variolavirus, vaccinia virus, an adenovirus, a cytomegalovirus, herpes simplexvirus 1, herpes simplex virus 2, Epstein Barr virus, BK virus, JC virus,feline leukemia virus and feline immunodeficiency virus, therebyinhibiting growth of the cell transformed by a virus.

Methods of Synthesis

In another aspect, there is provided a method for synthesis of compoundsof Formula (I), as depicted in Scheme 1 following. For Scheme 1,substituents B_(Nuc), X, R and L are as described for Formula (I)herein.

In another aspect, there is provided a method for synthesis of compoundsof Formula (Ia), as depicted in Scheme 1a following. For Scheme 1a,substituents B_(Nuc(a)), X^(a), R^(a) and L^(a) are as described forFormula (Ia) herein.

The method includes reacting a suitably substituted ANP monoester withR—OH or R^(a)—OH in the presence of a coupling agent such as(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®) to give a diester. Methods for preparing the ANP monoesters arewell known. For examples, see Beadle, J. R et al. Journal of MedicinalChemistry, 2006, 49:2010-2015, and Valiaeva, N. et al. AntiviralResearch, 2006, 72:10-19. The use of PYBOP® for synthesis of phosphonatediesters was first described in Campagne, J-M. et al. TetrahedronLetters, 1993, 34:6743-6744. Other coupling/condensation reagents, forexample uronium, carbodiimide, imidazolium and acid chloride reagents,may also be used (for a review of coupling agents see, e.g., El-Faham,A. & Albericio, F. Chemical Reviews, 2011, 111:6557-6602).

In another aspect, there is provided a method for synthesis of compoundsof Formula (I). The method includes the steps provided in Scheme 2following:

In the method of Scheme 2, B_(Nuc) is a naturally occurring purine orpyrimidine base, or analog thereof; L is a lipophilic promoiety,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, or O-substituted glyceryl having the formula—CH₂CH(OR¹)—CH₂(OR²) (II), wherein R¹ and R² are independentlysubstituted or unsubstituted alkyl or substituted or unsubstituted aryl;R is substituted or unsubstituted lower alkyl, substituted orunsubstituted lower heteroalkyl, substituted or unsubstituted lowercycloalkyl, substituted or unsubstituted lower heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstituted lowerheteroaryl; X is hydrogen, substituted or unsubstituted lower alkyl, orsubstituted or unsubstituted lower heteroalkyl; and Y is a leavinggroup.

The method includes: 1) contacting a protected nucleoside B_(Nuc) withstructure of Formula (2-1) with an ester with structure of Formula (2-2)in the presence of a strong base under conditions suitable to afford amonoester with structure of Formula (2-3); and 2) reacting the monoesterso formed with structure of Formula (2-3) with L-OH in the presence of acoupling agent as known in the art, thereby synthesizing a compound withstructure of Formula (I).

In another aspect, there is provided a method for synthesis of compoundsof Formula (Ia). The method includes the following as provided in Scheme2a. For Scheme 2a, substituents B_(Nuc(a)), X^(a), R^(a) and L^(a) areas described for Formula (Ia) herein, and Y^(a) can be a leaving group.

The method includes: 1) contacting a protected nucleoside B_(Nuc(a))with structure of Formula (2-1a) with an ester with structure of Formula(2-2a) in the presence of a strong base under conditions suitable toafford a monoester with structure of Formula (2-3a); and 2) reacting themonoester so formed with structure of Formula (2-3a) with L^(a)-OH inthe presence of a coupling agent as known in the art, therebysynthesizing a compound with structure of Formula (Ia).

In embodiments, the method includes the steps provided in Scheme 2-1following, specifically, contacting a suitably protected nucleoside(general structure 2-1 where B_(Nuc) is a naturally occurring ormodified purine or pyrimidine base, with an ester of general structure2-2 (where Y is a leaving group such as p-toluenesulfonyl,methanesulfonyl, trifluoromethanesulfonyl, bromo, iodo, or the like) inthe presence of a strong base and suitable solvent to yield ANPmonoesters of Formula 2-3, and secondly, reacting ANP monoester 2-3 withL-OH (i.e., hydroxy form of L) in the presence of a coupling agent suchas PYBOP® to give a diester of Formula (I).

In another aspect, there is provided method for synthesis of a compoundwith structure of Formula (I) according to Scheme 2-1. B_(Nuc), X, R andL are as described for Formula (I) herein, and Y can be a leaving group;said method comprising: contacting a compound of Formula (2-1) that hasa protected B_(Nuc) with a compound of Formula (2-2) in the presence ofa strong base to form a compound of Formula (2-3); and reacting thecompound of Formula (2-3) with L-OH in the presence of a coupling agentto form the compound of Formula (I).

In another aspect, there is provided method for synthesis of a compoundwith structure of Formula (Ia) according to Scheme 2-1a. For thismethod, B_(Nuc(a)) can be a naturally occurring purine, a naturallyoccurring pyrimidine, a non-naturally occurring purine or anon-naturally occurring pyrimidine; L^(a) can be an unsubstituted C₁₂₋₂₄alkyl, an unsubstituted C₁₃₋₂₉ heteroalkyl or a substituted glycerylmoiety, wherein the glyceryl moiety can be substituted with one or moregroups selected from an unsubstituted C₁₃₋₂₉ alkyl, an unsubstitutedC₁₃₋₂₉ heteroalkyl, a substituted or unsubstituted aryl(C₁₋₆ alkyl), asubstituted or unsubstituted heteroaryl(C₁₋₆ alkyl) and a substituted orunsubstituted heterocycloalkyl(C₁₋₆ alkyl); R^(a) can be selected froman unsubstituted C₁₋₆ alkyl, a substituted or unsubstituted aryl, asubstituted or unsubstituted heteroaryl, a substituted or unsubstitutedheterocycloalkyl, a substituted or unsubstituted aryl(C₁₋₆ alkyl), asubstituted or unsubstituted heteroaryl(C₁₋₆ alkyl) and a substituted orunsubstituted heterocycloalkyl(C₁₋₆ alkyl); X^(a) can be hydrogen, anunsubstituted C₁₋₆ alkyl, a halogen substituted C₁₋₆ alkyl, a hydroxysubstituted C₁₋₆ alkyl or an unsubstituted C₁₋₆ alkoxy; and Y^(a) can bea leaving group; said method comprising: contacting a compound ofFormula (2-1a) that has a protected B_(Nuc(a)) with a compound ofFormula (2-2a) in the presence of a strong base to form a compound ofFormula (2-3a); and reacting the compound of Formula (2-3a) withL^(a)-OH in the presence of a coupling agent to form the compound ofFormula (Ia).

In another aspect, there is provided a method for synthesizing acompound of Formula (I) as described in Scheme 3 following. For Scheme3, substituents B_(Nuc), X, R and L are as described for Formula (I)herein.

The method includes contacting a suitably protected nucleoside (generalstructure 3-1 where B_(Nuc) is a naturally occurring or modified purineor pyrimidine base), with a diester of general structure 3-2 (where Y isa leaving group such as p-toluenesulfonyl, methanesulfonyl,trifluoromethanesulfonyl, bromo, iodo, or the like) in the presence of astrong base and suitable solvent to yield a compound of Formula (I).

In another aspect, there is provided a method for synthesizing acompound of Formula (Ia) as described in Scheme 3a. For Scheme 3a,substituents B_(Nuc(a)), X^(a), R^(a) and L^(a) are as described forFormula (Ia) herein, and Y^(a) is a leaving group.

The method includes contacting a suitably protected nucleoside (3-1a),with a diester 3-2 (where Y^(a) is a leaving group such asp-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, bromo,iodo, or the like) in the presence of a strong base and suitable solventto yield a compound of Formula (Ia).

Pharmaceutical Compositions

In another aspect, there is provided a pharmaceutical compositionsincluding a compound of Formula (I) and/or a compound of Formula (Ia) incombination with a pharmaceutically acceptable excipient (e.g.,carrier).

The terms “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient” and the like as used herein refer topharmaceutical excipients, for example, pharmaceutically,physiologically, acceptable organic or inorganic carrier substancessuitable for enteral or parenteral application that do not deleteriouslyreact with the active agent. Suitable pharmaceutically acceptablecarriers include water, salt solutions (such as Ringer's solution),alcohols, oils, gelatins, and carbohydrates such as lactose, amylose orstarch, fatty acid esters, hydroxymethycellulose, and polyvinylpyrrolidine. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds described herein.

The compounds described herein can be administered alone or can becoadministered to the subject. Coadministration is meant to includesimultaneous or sequential administration of the compounds individuallyor in combination (more than one compound). The preparations can also becombined, when desired, with other active substances (e.g., to reducemetabolic degradation).

Formulations

The compounds described herein can be prepared and administered in awide variety of oral, parenteral, and topical dosage forms. Thus, thecompounds described herein can be administered by injection (e.g.intravenously, intramuscularly, intracutaneously, subcutaneously,intraduodenally, or intraperitoneally). Also, the compounds describedherein can be administered by inhalation, for example, intranasally.Additionally, the compounds described herein can be administeredtransdermally. It is also envisioned that multiple routes ofadministration (e.g., intramuscular, oral, transdermal) can be used toadminister the compounds described herein. Accordingly, pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier orexcipient and one or more compounds are contemplated.

For preparing pharmaceutical compositions, pharmaceutically acceptablecarriers can be either solid or liquid. Solid form preparations includepowders, tablets, pills, capsules, cachets, suppositories, anddispersible granules. A solid carrier can be one or more substances thatmay also act as diluents, flavoring agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid in a mixture with thefinely divided active component. In tablets, the active component ismixed with the carrier having the necessary binding properties insuitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain from 5% to 70% of the activecompound. Suitable carriers are magnesium carbonate, magnesium stearate,talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoabutter, and the like. The term “preparation” is intended to include theformulation of the active compound with encapsulating material as acarrier providing a capsule in which the active component with orwithout other carriers, is surrounded by a carrier, which is thus inassociation with it. Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets, and lozenges can be used assolid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

When parenteral application is needed or desired, particularly suitableadmixtures are injectable, sterile solutions, preferably oily or aqueoussolutions, as well as suspensions, emulsions, or implants, includingsuppositories. In particular, carriers for parenteral administrationinclude aqueous solutions of dextrose, cyclodextrins, saline, purewater, ethanol, glycerol, propylene glycol, peanut oil, sesame oil,polyoxyethylene-block polymers, and the like. Ampoules are convenientunit dosages. The compounds described herein can also be incorporatedinto liposomes or administered via transdermal pumps or patches.Pharmaceutical admixtures suitable for use include those described, forexample, in PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub. Co., Easton,Pa.) and WO 96/05309, the teachings of both of which are herebyincorporated by reference.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and/or thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form. In embodiments, the unit dosage form can be in theform of an applicator pre-filled with a pharmaceutical compositiondescribed herein (for example, a pharmaceutical composition thatcontains an effective amount of a compound of Formula (I) and/or acompound of Formula (Ia)). In embodiments, the pre-filled applicator canbe filled with a pharmaceutical composition in the form of a cream, agel or an ointment that contains a compound described herein (forexample, a compound of Formula (I) and/or a compound of Formula (Ia)).

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to1000 mg, most typically 10 mg to 500 mg, according to the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

Some compounds may have limited solubility in water and therefore mayrequire a surfactant or other appropriate co-solvent in the composition.Such co-solvents include: Polysorbate 20, 60, and 80; PLURONIC® F-68,F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Suchco-solvents are typically employed at a level between about 0.01% andabout 2% by weight.

Viscosity greater than that of simple aqueous solutions may be desirableto decrease variability in dispensing the formulations, to decreasephysical separation of components of a suspension or emulsion offormulation, and/or otherwise to improve the formulation. Such viscositybuilding agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxy propyl methylcellulose,hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propylcellulose, chondroitin sulfate and salts thereof, hyaluronic acid andsalts thereof, and combinations of the foregoing. Such agents aretypically employed at a level between about 0.01% and about 2% byweight.

The compositions may additionally include components to providesustained release and/or comfort. Such components include high molecularweight, anionic mucomimetic polymers, gelling polysaccharides, andfinely-divided drug carrier substrates. These components are discussedin greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and4,861,760. The entire contents of these patents are incorporated hereinby reference in their entirety for all purposes.

Effective Dosages

Pharmaceutical compositions include compositions wherein the activeingredient is contained in a therapeutically effective amount, i.e., inan amount effective to achieve its intended purpose. The actual amounteffective for a particular application will depend, inter alia, on thecondition being treated. For example, when administered in methods totreat cancer, such compositions will contain an amount of activeingredient effective to achieve the desired result (e.g., decreasing thenumber of cancer cells in a subject).

The dosage and frequency (single or multiple doses) of compoundadministered can vary depending upon a variety of factors, includingroute of administration; size, age, sex, health, body weight, body massindex, and diet of the recipient; nature and extent of symptoms of thedisease being treated; presence of other diseases or otherhealth-related problems; kind of concurrent treatment; and complicationsfrom any disease or treatment regimen. Other therapeutic regimens oragents can be used in conjunction with the methods and compoundsdescribed herein.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Therapeuticallyeffective amounts for use in humans may subsequently be estimated fromanimal models using conventional techniques that are confirmed orrefined in actual clinical trials.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient shouldbe sufficient to effect a beneficial therapeutic response in the patientover time. The size of the dose also will be determined by theexistence, nature, and extent of any adverse side effects. Generally,treatment is initiated with smaller dosages, which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached. In one embodiment, the dosage range is 0.001% to 10% w/v. Inanother embodiment, the dosage range is 0.1% to 5% w/v.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is entirely effective to treat the clinicalsymptoms demonstrated by the particular patient. This planning shouldinvolve the careful choice of active compound by considering factorssuch as compound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration, and the toxicity profile of the selected agent.

Toxicity

The ratio between toxicity and therapeutic effect for a particularcompound is its therapeutic index and can be expressed as the ratiobetween LD₅₀ (the amount of compound lethal in 50% of the population)and ED₅₀ (the amount of compound effective in 50% of the population).Compounds that exhibit high therapeutic indices are preferred.Therapeutic index data obtained from cell culture assays and/or animalstudies can be used in formulating a range of dosages for use in humans.The dosage of such compounds preferably lies within a range of plasmaconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. See, e.g. Fingl etal., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch. 1, p. 1, 1975.The exact formulation, route of administration, and dosage can be chosenby the individual physician in view of the patient's condition and theparticular method in which the compound is used.

EXAMPLES

General Chemistry Methods:

All reagents were of commercial quality and used without furtherpurification unless indicated otherwise. Chromatographic purificationwas done using the flash method with silica gel 60 (EMD Chemicals, Inc.,230-400 mesh). ¹H NMR spectra were recorded on a Varian HGspectrophotometer operating at 400 MHz and are reported in units ofparts per million (ppm) relative to internal tetramethylsilane at 0.00ppm. Routine electrospray ionization mass spectra (ESI-MS) were recordedon a Finnigan LCQ DECA spectrometer, and high resolution mass spectra(HRMS) were recorded on an Agilent 6230 Accurate-Mass TOFMS massspectrometer in ESI negative mode. Purity of the target compounds wascharacterized by high performance liquid chromatography (HPLC) using aBeckman Coulter SYSTEM GOLD® chromatography system. The analyticalcolumn was PHENOMENEX® SYNERGI™ Polar-RP (4.6×150 mm) equipped with aSECURITYGUARD™ protection column. Mobile phase A was 95% water/5%methanol and mobile phase B was 95% methanol/5% water. At a flow rate of0.8 mL/min, isocratic elution was used. Compounds were detected byultraviolet light (UV) absorption at 274 nm. Homogeneity of the targetcompounds was also confirmed by thin layer chromatography (TLC) usingAnaltech silica gel-GF (250 μm) plates and the solvent system:CHCl₃/MeOH/con NH₄OH/H₂O (70:30:3:3 v/v). TLC results were visualizedwith UV light, phospray (SUPELCO®, Bellefonte, Pa., USA) and charring at400° C.

Example 1. Preparation of benzyl octadecyloxyethyl9-[2-(phosphonomethoxy) ethyl]guanine, 1-(Rp,Sp) (Cmpd 1, Bn-ODE-PMEG)

To a solution of octadecyloxyethyl 9-[2-(phosphonomethoxy)ethyl]guanine(ODE-PMEG) [prepared according to: Valiaeva, N. et al.; AntiviralResearch, 2006, 72:10-19] (0.21 g, 0.35 mmol),(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 0.27 g, 0.525 mmol) and anhydrous benzyl alcohol (0.05 ml,0.525 mmol) in dry N,N-DMF, diisopropylethylamine (DIEA, 0.24 ml, 1.4mmol) was added. The mixture was stirred at room temperature for 30 min.The solvents were evaporated in vacuo. The residue was dissolved inethyl acetate (50 ml) and extracted with saturated sodium bicarbonate(2×10 ml). The ethyl acetate layer was evaporated, and then the residuewas adsorbed on silica gel and purified by flash column chromatography.Elution with CH₂Cl₂/MeOH (0-5%) gave 0.15 g (62%) of Cmpd 1 as a whitepowder. ¹H NMR (CDCl₃/methanol-d₄) δ 7.56 (s, 1H); 7.35-7.40 (m, 5H);5.08 (dd, J=9 Hz, J1=2 Hz, 2H); 4.19 (t, J=7 Hz, 2H); 4.09-4.17 (m, 2H);3.87 (t, J=5 Hz, 2H), 3.85 (dd, J=8 Hz, J1=2 Hz, 2H); 3.57 (t, J=5 Hz,2H); 3.44 (t, J=7 Hz, 2H); 1.50-1.60 (m, 2H); 1.20-1.38 (m, 30H); 0.89(t, J=7 Hz, 3H). MS (EI): 676.34 (M+H)⁺, 698.41 (M+Na)⁺.

Example 2. Resolution of benzyl octadecyloxyethyl9-[2-(phosphonomethoxy) ethyl]guanine P-Chiral Enantiomers

Bn-ODE-PMEG of Example 1 was obtained as a mixture of enantiomersbecause of the chirality at phosphorus. The enantiomers were separatedon a Lux™ Cellulose-1 column (Phenomenex®, Torrance, Calif. USA) usingreverse phase conditions (mobile phase of 50:50:0.1 20 mMAmmAc:AcN:TFA). The absolute stereochemistry of the P-chiral enantiomerswas not determined. The preparative chromatographic resolution of thematerial obtained in Example 1 provided two enantiomers that arecharacterized as 1a (fast eluting enantiomer) and 1b (slow elutingenantiomer). An example chromatogram is provided in the FIGURE.

In the following examples, preparation of the racemic mixture isdescribed, however, the method of Example 2, or modifications thereofknown in the art, can be used to resolve each into optically activeenantiomers or diastereomers as needed.

Example 3. Preparation of benzyl octadecyloxyethyl9-[2-(phosphonomethoxy) ethyl]adenine (Cmpd 2, Bn-ODE-PMEA)

To a solution of octadecyloxyethyl 9-[2-(phosphonomethoxy)ethyl]adenine(ODE PMEA) [prepared according to: Valiaeva, N. et al. AntiviralResearch 2006, 72:10-19] (0.2 g, 0.35 mmol),(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 0.27 g, 0.525 mmol), anhydrous benzyl alcohol (0.05 ml, 0.525mmol) in dry N,N-DMF, diisopropylethylamine (DIEA, 0.24 ml, 1.4 mmol)was added. The mixture was stirred at room temperature for 30 min. Thesolvents were evaporated. The residue was dissolved in ethyl acetate (50ml) and washed with a saturated solution of sodium bicarbonate (2×10ml). The ethyl acetate layer was evaporated, and then the residue waspurified by column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%)to give 0.12 g (50%) of compound 2. ¹H NMR (CDCl₃/methanol-d₄) δ 8.25(s, 1H); 7.99 (s, 1H); 7.30-7.40 (m, 5H); 5.07 (dd, J=9 Hz, J1=2 Hz,2H); 4.38 (t, J=7 Hz, 2H); 4.08-4.18 (m, 2H); 3.88 (t, J=5 Hz, 2H), 3.83(dd, J=8 Hz, J1=2 Hz, 2H); 3.56 (t, J=5 Hz, 2H); 3.42 (t, J=7 Hz, 2H);1.50-1.60 (m, 2H); 1.20-1.38 (m, 30H); 0.88 (t, J=7 Hz, 3H). MS (EI):660.55 (M+H)⁺.

Example 4. Preparation of benzyl octadecyloxyethyl9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl] adenine (Cmpd 218,Bn-ODE-(S)-HPMPA)

Method 1:

To a solution of octadecyloxyethyl9-(S)-[3-trityloxy-2-(phosphonomethoxy) propyl]-N⁶-trityladenine(prepared as described in: Beadle, J. R. et al. Journal of MedicinalChemistry 2006, 49:2010-2015) (0.42 g, 0.38 mmol),(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 0.30 g, 0.58 mmol), benzyl alcohol (0.06 ml, 0.58 mmol) in dryN,N-DMF (2 ml), diisopropylethylamine (DIEA, 0.4 ml, 1.52 mmol) wasadded. The mixture was stirred at room temperature for 30 min. Thesolvents were evaporated. The residue was dissolved in ethyl acetate (50ml), and then washed with saturated solution of sodium bicarbonate (2×10ml). Ethyl acetate was evaporated, and the residue was purified bycolumn chromatography on silica gel using CH₂Cl₂/MeOH (0-5%) to give0.23 g (51%) of the product. ¹H NMR (CDCl₃/methanol-d₄) δ 7.89 (s, 1H);7.16-7.40 (m, 36H); 5.03 (dd, J=9 Hz, J1=2 Hz, 2H); 4.27-4.44 (m, 2H);4.06-4.14 (m, 1H); 3.91-4.04 (m, 2H), 3.83 (dd, J=8 Hz, J1=2 Hz, 2H);3.40-3.50 (m, 2H); 3.27-3.40 (m, 4H); 1.42-1.58 (m, 2H); 1.18-1.38 (m,30H); 0.88 (t, J=7 Hz, 3H). MS (EI): 1174.27 (M+H)⁺.

The protected intermediate (0.13 g, 0.11 mmol) was added to 80% aqacetic acid (10 ml) and stirred at 30° C. for 3 h. After cooling, thesolvent was evaporated and the residue was purified by columnchromatography on silica gel to give compound 218 (0.04 g, 52% yield).¹H NMR (CDCl₃/methanol-d₄) δ 8.25 (s, 1H); 7.89 (s, 1H); 7.26-7.38 (m,5H); 5.09 (dd, J=9 Hz, J1=2 Hz, 2H); 4.28-4.43 (m, 2H); 4.06-4.18 (m,1H); 3.95-4.05 (m, 2H), 3.80 (dd, J=8 Hz, J1=2 Hz, 2H); 3.50-3.60 (m,2H); 3.25-3.38 (m, 4H); 1.49-1.60 (m, 2H); 1.10-1.40 (m, 30H); 0.88 (t,J=7 Hz, 3H). MS (EI): 690.49 (M+H)⁺, 712.47 (M+H)⁺.

Method 2:

A mixture of 9-(S)-[3-trityloxy-2-hydroxypropyl]-N⁶-trityladenine[prepared as in: Webb, R. R., Nucleosides & Nucleotides, 1989, 8:619-24](1.4 g, 2.0 mmol) and sodium tert-butoxide (0.39 g, 4 mmol) in dryN,N-DMF (10 ml) were stirred at room temperature for 30 min, then benzylp-toluenesulfonyloxymethylphosphonate (0.94 g, 2.5 mmol, see Example 6)was added. The mixture was stirred at 80° C. overnight. The solvent wasevaporated, and then the residue was purified by column chromatographyon silica gel to give benzyl9-(S)-[3-trityloxy-2-(phosphonomethoxy)propyl]-N⁶-trityladenine 0.75 g(42%). ¹H NMR (CDCl₃/methanol-d₄) δ 8.09 (s, 1H); 7.88 (s, 1H);7.08-7.60 (m, 30H); 4.84-4.88 (m, 2H); 4.20-4.30 (m, 2H); 3.78-4.90 (m,1H); 3.50-3.72 (m, 2H), 2.99-3.18 (m, 2H).

To a solution of this intermediate (0.2 g, 0.22 mmol),(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 0.17 g, 0.33 mmol) and octadecyloxyethanol (0.10 g, 0.33 mmol)in dry N,N-DMF (2 ml), diisopropylethylamine (DIEA, 0.15 ml, 0.88 mmol)was added. The mixture was stirred at room temperature for 30 min andthe solvent was evaporated. The residue was dissolved in ethyl acetate(50 ml) and washed with saturated solution of sodium bicarbonate (2×10ml). The ethyl acetate layer was evaporated, and then the residue waspurified by column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%)to give 0.15 g (58%) of the product. ¹H NMR (CDCl₃/methanol-d₄) δ: 7.93(s, 1H); 7.87 (s, 1H); 7.16-7.42 (m, 35H); 5.00 (dd, J=9 Hz, J₁=2 Hz,2H); 4.27-4.44 (m, 2H); 4.06-4.14 (m, 1H); 3.91-4.04 (m, 2H), 3.83 (dd,J=8 Hz, J₁=2 Hz, 2H); 3.40-3.50 (m, 2H); 3.27-3.40 (m, 4H); 1.42-1.58(m, 2H); 1.18-1.38 (m, 30H); 0.88 (t, J=7 Hz, 3H). MS (EI): 1174.29(M+H)⁺; 1196.52 (M+Na)⁺.

The protected compound (0.15 g, 0.13 mmol) was treated with 80% aqacetic acid (10 ml) at 30° C. for 3 h. The solvents were evaporated, andthen the residue was purified by column chromatography on silica gel togive compound 218 (0.06 g, 68%). ¹H NMR (CDCl₃/methanol-d₄) δ: 8.24 (s,1H); 7.52 (s, 1H); 7.34-7.38 (m, 5H); 5.06 (dd, J=9 Hz, J₁=2 Hz, 2H);4.28-4.46 (m, 2H); 4.06-4.16 (m, 2H); 3.95-4.16 (m, 1H), 3.76-3.87 (m,2H); 3.52-3.66 (m, 4H); 3.39-3.48 (m, 2H); 1.49-1.60 (m, 2H); 1.20-1.40(m, 30H); 0.89 (t, J=7 Hz, 3H). MS (EI): 690.47 (M+H)⁺, 712.45 (M+Na)⁺.

Example 5. Preparation of isopropylidene glyceryl octadecyloxyethyl9-(2-phosphonomethoxyethyl)guanine

To a suspension of octadecyloxyethyl9-[2-(phosphonomethoxy)ethyl]guanine (ODE PMEG)) [prepared according to:Valiaeva, N. et al.; Antiviral Research, 2006, 72:10-19] (0.18 g, 0.30mmol), oxalyl chloride (0.56 ml, 0.48 mmol) in dry toluene (5 ml), DMF(0.06 ml) was added. The mixture was stirred at room temperature for 1h. The solvent was evaporated in vacuum and co-evaporated with toluene(2×10 ml). The residue was dissolved in toluene (5 ml) andisopropylidene glycerol (0.09 g, 0.6 mmol) was added. The mixture wasstirred at room temperature overnight. A solution of saturated sodiumbicarbonate (5 ml) was added, and the mixture was stirred for 30 min.The toluene fraction was evaporated and purified by columnchromatography on silica gel to give 0.05 g of IPG-ODE-PMEG (23%). ¹HNMR (CDCl₃/methanol-d₄) δ: 8.91 (s, 1H); 8.15 (s, 1H); 4.44-4.52 (m,2H); 4.18-4.34 (m, 2H); 4.13-4.18 (m, 1H); 4.02-4.13 (m, 2H); 3.95-4.18(m, 2H); 3.68-3.84 (m, 2H); 3.60-3.67 (m, 2H); 3.44-3.52 (m, 2H); 1.42(t, J=7 Hz, 3H); 1.36 (t, J=7 Hz, 3H); 1.22-1.34 (m, 30H), 0.89 (t, J=7Hz, 3H). MS (EI): 700.37 (M+H)⁺, 722.43 (M+Na)⁺.

Example 6. Preparation of benzyl p-toluenesulfonyloxymethyl phosphonate,sodium salt

Diethyl p-toluenesulfonyloxymethyl phosphonate (3.2 g, 9.9 mmol) wasdissolved in N,N-DMF (10 ml) and then bromotrimethylsilane (10 ml) wasadded. The mixture was stirred at room temperature overnight. Thesolvent was evaporated, and co-evaporated with toluene (2×10 ml). Anethanol/water mixture (10 ml) was added, and then mixture was stirredfor 30 min at room temperature. The solvents were evaporated andco-evaporated with toluene (2×10 ml). The residue was suspended intoluene (50 ml), and then oxalyl chloride (1.3 ml, 15.0 mmol) was addedfollowed by N,N-DMF (0.01 ml). The mixture was stirred at roomtemperature for 1 h. The solvents were evaporated and co-evaporated withtoluene (2×10 ml). The residue was suspended in toluene (25 ml), andthen anhydrous benzyl alcohol (1.5 ml, 15.0 mmol) was added. The mixturewas stirred at room temperature overnight. A solution of saturatedsodium bicarbonate (15 ml) was added, and then the mixture was stirredfor 30 min. The toluene fraction was evaporated, and the residue waspurified by column chromatography on silica gel to give 2.94 g of benzylp-toluenesulfonyloxymethyl phosphonate, sodium salt (81%). ¹H NMR(CDCl₃/methanol-d₄) δ: 7.72 (d, J=8 Hz, 2H); 7.30-7.33 (m, 7H); 4.88 (d,J=7 Hz, 2H); 4.02 (d, J=9 Hz, 2H); 2.44 (s, 3H).

Example 7. Preparation of benzyl 1-O-octadecyl-2-O-benzyl-sn-glyceryl9-(S)-[(3-hydroxypropyl-2-phosphonomethoxy)propyl]adenine (Cmpd 230,Bn-ODBG-(S)-HPMPA)

To a solution of benzyl9-(S)-[3-trityloxy-2-(phosphonomethoxy)propyl]-N⁶-trityladenine(prepared as in Example 4, method 2) (0.4 g, 0.44 mmol),(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 0.27 g, 0.51 mmol), 1-O-octadecyl-2-O-benzyl-sn-glycerol (0.22g, 0.51 mmol) in dry N,N-DMF (1 ml), diisopropylethylamine (DIEA, 0.30ml, 1.7 mmol) was added. The mixture was stirred at room temperature for30 min. The solvents were evaporated. The residue was dissolved in ethylacetate (50 ml), and then washed with a solution of saturated sodiumbicarbonate (2×10 ml). The ethyl acetate layer was evaporated and thenthe residue was purified by column chromatography on silica gel usingCH₂Cl₂/MeOH (0-5%) to give 0.15 g (58%) of the product. ¹H NMR(CDCl₃/methanol-d₄) δ: 7.88 (s, 1H); 7.87 (s, 1H); 7.19-7.42 (m, 40H);4.95-5.03 (m, 2H); 4.57-4.60 (m, 2H); 4.29-4.39 (m, 2H); 4.16-4.28 (m,2H), 4.00-4.12 (m, 1H); 3.90-3.98 (m, 1H); 3.65-3.81 (m, 4H); 3.45-3.49(m, 2H); 1.46-1.53 (m, 2H); 1.22-1.32 (m, 30H); 0.88 (t, J=7 Hz, 3H). MS(EI): 1294.27 (M+H)⁺; 1316.57 (M+Na)⁺.

The protected compound (0.33 g, 0.13 mmol) was treated with 80% aqacetic acid (20 ml) at 30° C. for 3 h. The solvents were then evaporatedand the residue was purified by column chromatography on silica gel togive compound 230 (0.13 g, 65%). ¹H NMR (CDCl₃/methanol-d₄) δ: 8.22 (s,1H); 7.65 (s, 1H); 7.27-7.35 (m, 10H); 4.99-5.04 (m, 2H); 4.58-4.66 (m,2H); 4.33-4.43 (m, 1H); 4.16-4.33 (m, 2H), 3.94-4.12 (m, 2H); 3.80-3.88(m, 1H); 3.68-3.78 (m, 2H); 3.38-3.62 (m, 4H); 1.50-1.58 (m, 2H);1.22-1.38 (m, 30H); 0.89 (t, J=7 Hz, 3H). MS (EI): 810.47 (M+H)⁺, 832.44(M+Na)⁺.

Example 8. Preparation of benzyl octadecyloxyethyl1-(S)-[(3-hydroxy-2-phosphonomethoxy)propyl]cytosine (Cmpd 219,Bn-ODE-(S)-HPMPC)

A mixture of1-(S)-[3-trityloxy-2-hydroxypropyl]-N⁴-monomethoxytritylcytosine[prepared as described in: Beadle, J. R., et al., PCT Int. Appl. WO2005/087788 A2, published Sep. 22, 2005] (1.84 g, 2.63 mmol) and sodiumtert-butoxide (1.24 g, 3.29 mmol) in dry DMF (20 ml) were stirred atroom temperature for 30 min. Benzylp-toluenesulfonyloxymethylphosphonate (0.94 g, 2.5 mmol, see Example 6)were added and the mixture was stirred at 80° C. overnight. The solventwas evaporated, and the residue was purified by column chromatography onsilica gel to give benzyl1-(S)-[3-trityloxy-2-(phosphonomethoxy)propyl]-N⁴-monomethoxytritylcytosine1.25 g (52%). ¹H NMR (CDCl₃/methanol-d₄) δ: 7.12-7.48 (m, 24H); 7.05 (d,J=9 Hz, 1H); 6.79 (d, J=9 Hz, 1H); 4.70 (dd, J₁=30 Hz, J₂=6 Hz, 2H);4.20-4.30 (m, 2H); 3.78-4.90 (m, 1H); 3.77 (s, 3H); 3.50-3.72 (m, 2H),2.99-3.18 (m, 2H). (EI): 883.99 (M+H)⁺, 906.22 (M+Na)⁺.

To a solution of this intermediate (0.6 g, 0.66 mmol),(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 0.52 g, 0.99 mmol), octadecyloxyethanol (0.31 g, 0.52 mmol) indry DMF (5 ml), diisopropylethylamine (DIEA, 0.46 ml, 2.65 mmol) wasadded. The mixture was stirred at room temperature for 30 min and thenthe solvents were evaporated. The residue was dissolved in ethyl acetate(50 ml), and washed with saturated solution of sodium bicarbonate (2×10ml). Ethyl acetate was evaporated, and the residue was purified bycolumn chromatography on silica gel using CH₂Cl₂/MeOH (0-5%) to give theproduct. ¹H NMR (CDCl₃/methanol-d₄) δ: 7.18-7.44 (m, 34H); 7.13 (dd,J=14 Hz, J₂=7 Hz, 1H); 6.85 (dd, J₁=14 Hz, J₂=7 Hz, 1H); 5.00 (dd, J₁=8Hz, J₂=3 Hz, 2H); 4.04-4.12 (m, 2H); 3.88-3.95 (m, 1H); 3.80 (s, 3H);3.58-3.79 (m, 4H); 3.45-3.57 (m, 2H); 3.16-3.22 (m, 1H); 3.02-3.08 (m,1H); 1.43-1.52 (m, 2H); 1.08-1.38 (m, 30H); 0.88 (t, J=7 Hz, 3H). (EI):1180.10 (M+H)⁺, 1202.57 (M+Na)⁺.

The protected compound (0.44 g, 0.37 mmol) was treated with 80% aceticacid (20 ml) at 30° C. for 3 h. The solvents were evaporated, and theresidue was purified by column chromatography to give compound 219 (0.16g, 64%). ¹H NMR (CDCl₃/methanol-d₄) δ: 7.40-7.42 (m, 5H); 7.38 (dd,J₁=14 Hz, J₂=7 Hz, 1H); 5.73 (dd, J₁=14 Hz, J₂=7 Hz, 1H); 5.12 (dd, J₁=8Hz, J₂=3 Hz, 2H); 4.10-4.20 (m, 2H), 3.99-4.10 (m, 2H), 3.50-3.80 (m,7H), 3.40-3.50 (m, 2H); 1.50-1.62 (m, 2H), 1.20-1.40 (m, 30H), 0.89 (t,J=7 Hz, 3H). Mass spec (ESI): 666.54 (M+H)⁺, 688.52 (M+Na)⁺.

Example 9. Preparation of benzyl 1-O-octadecyl-2-O-benzyl-sn-glyceryl1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (Cmpd 231, Bn-ODBG(S)-HPMPC)

To a solution of the intermediate from Example 8, benzyl1-(S)-[3-trityloxy-2-(phosphonomethoxy)propyl] N⁴-monomethoxytritylcytosine (0.57 g, 0.63 mmol),(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 0.49 g, 0.95 mmol) and 1-O-octadecyl-2-O-benzyl-sn-glycerol(0.41 g, 0.95 mmol) in dry DMF (5 ml), diisopropylethylamine (DIEA, 0.44ml, 2.52 mmol) was added. The mixture was stirred at room temperaturefor 30 min. The solvents were evaporated. The residue was dissolved inethyl acetate (50 ml) and washed with saturated solution of sodiumbicarbonate (2×10 ml). Ethyl acetate was evaporated, and the residue waspurified by column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%)to give 0.30 g (36%) of the product. ¹H NMR (CDCl₃/methanol-d₄) δ:7.19-7.45 (m, 39H); 7.15 (dd, J₁=14 Hz, J₂=7 Hz, 1H); 6.82 (dd, J₁=14Hz, J₂=7 Hz, 1H); 5.00 (dd, J₁=8 Hz, J₂=3 Hz, 2H); 4.69-4.71 (m, 2H);4.05 (s, 3H), 3.96-4.05 (m, 2H); 3.82-3.90 (m, 1H); 3.50-3.80 (m, 4H);3.40-3.53 (m, 2H); 3.24-3.40 (m, 4H); 3.02-3.08 (m, 1H); 1.43-1.50 (m,2H); 1.20-1.40 (m, 30H); 0.88 (t, J=7 Hz, 3H). (EI): 1301.06 (M+H)⁺,1322.58 (M+Na)⁺.

The protected compound (0.30 g, 0.23 mmol) was then treated with 80%acetic acid (20 ml) at 30° C. for 3 h. The solvents were evaporated, andthe residue was purified by column chromatography to give compound 231(0.10 g, 55%). ¹H NMR (CDCl₃/methanol-d₄) δ: 7.31-7.40 (m, 10H); 7.28(dd, J₁=14 Hz, J₂=7 Hz, 1H); 5.66 (dd, J₁=14 Hz, J₂=7 Hz, 1H); 5.07 (dd,J₁=8 Hz, J₂=3 Hz, 2H); 4.63-4.66 (m, 2H), 4.18-4.27 (m, 2H), 4.02-4.14(m, 2H), 3.90-3.98 (m, 2H), 3.40-3.84 (m, 8H); 1.50-1.62 (m, 2H),1.20-1.40 (m, 30H), 0.89 (t, J=7 Hz, 3H). Mass spec (ESI): 786.43(M+H)⁺, 808.41 (M+Na)⁺.

Example 10. Preparation of phenyl octadecyloxyethyl9-[2-(phosphonomethoxy) ethyl]guanine (Cmpd 19, Ph-ODE-PMEG)

To a solution of octadecyloxyethyl 9-[2-(phosphonomethoxy)ethyl]guanine(ODE-PMEG, 0.26 g, 0.44 mmol) [prepared according to: Valiaeva, N. etal. Antiviral Research 2006, 72:10-19],(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 0.34 g, 0.66 mmol), and phenol (0.06 g, 0.66 mmol) in anhydrousN,N-DMF, was added diisopropylethylamine (DIEA, 0.30 ml, 1.8 mmol). Themixture was stirred at room temperature for 30 min, and then the solventwas evaporated in vacuo. The residue was dissolved in ethyl acetate (50ml) and washed with saturated sodium bicarbonate (2×10 ml) solution. Theethyl acetate layer was evaporated, and the crude residue was purifiedby flash column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%) toafford 0.09 g (31%) of compound 19 as a white powder. ¹H NMR(CDCl₃/methanol-d₄) δ: 7.66 (s, 1H); 7.36 (t, J=8 Hz, 2H); 7.20 (t, J=7Hz, 1H); 7.13 (d, J=8 Hz, 2H); 4.23-4.30 (m, 4H); 4.03 (dd, J=8 Hz, J₁=2Hz, 2H); 3.93 (t, J=5 Hz, 2H); 3.61 (t, J=5 Hz, 2H), 3.41-3.45 (m, 2H);1.50-1.60 (m, 2H); 1.20-1.38 (m, 30H); 0.89 (t, J=7 Hz, 3H). MS (EI):662.43 (M+H)⁺, 684.39 (M+Na)⁺.

Example 11. Preparation of benzyl octadecyloxyethyl9-(S)-[3-methoxy-2-(phosphonomethoxy)propyl]adenine (Cmpd 146,Bn-ODE-(S)-MPMPA)

To a solution of octadecyloxyethyl9-[3-methoxy-2-(phosphonomethoxy)propyl]adenine (ODE-S)-MPMPA, 0.62 g,1.00 mmol) [prepared as described in: Valiaeva, N. et al. Bioorganic &Medicinal Chemistry, 2011, 19:4616-4625]),(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 0.78 g, 0.66 mmol), and benzyl alcohol (0.16 ml, 1.50 mmol) inanhydrous N,N-DMF, was added diisopropylethylamine (DIEA, 0.70 ml, 4.0mmol). The mixture was stirred at room temperature for 30 min, and thensolvents was evaporated in vacuo. The residue was dissolved in ethylacetate (50 ml) and then washed with saturated NaHCO₃ (2×10 ml). Theethyl acetate layer was evaporated, and the residue was purified byflash column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%) togive 0.29 g (41%) of compound 146. ¹H NMR (CDCl₃/methanol-d₄) δ 8.24 (d,J=5.50 Hz, 1H), 8.05 (d, J=7.33 Hz, 1H), 7.30-7.39 (m, 5H), 5.00-5.15(m, 2H); 4.40-4.45 (m, 1H); 4.28-4.36 (m, 1H); 4.00-4.18 (m, 3H);3.80-3.98 (m, 2H); 3.40-3.60 (m, 6H); 3.35 (s, 3H); 1.45-1.60 (m, 2H),1.22-1.36 (m, 30H), 0.89 (t, J=7 Hz, 3H). MS (EI): 704.52 (M+H)⁺, 726.45(M+Na)⁺.

Example 12. Preparation of phenyl octadecyloxyethyl9-(S)-[3-methoxy-2-(phosphonomethoxy)propyl]adenine (Cmpd 164,Ph-ODE-(S)-MPMPA)

To a solution of octadecyloxyethyl9-[3-methoxy-2-(phosphonomethoxy)propyl]adenine (ODE (S)-MPMPA, 0.62 g,1.00 mmol) [prepared as described in: Valiaeva, N. et al. Bioorganic &Medicinal Chemistry, 2011, 19:4616-4625],(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 0.78 g, 0.66 mmol), and phenol (0.14 g, 1.50 mmol) in dryN,N-DMF, was added diisopropylethylamine (DIEA, 0.70 ml, 4.0 mmol). Themixture was stirred at room temperature for 30 min, and then the solventwas evaporated in vacuo. The residue was dissolved in ethyl acetate (50ml), and then washed with saturated sodium bicarbonate (2×10 ml). Theethyl acetate layer was evaporated. The crude residue was purified byflash column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%) togive 0.29 g (41%) of compound 164 as an off white solid. ¹H NMR(CDCl₃/methanol-d₄) δ 8.23 (d, J=5.50 Hz, 1H), 8.05 (d, J=7.33 Hz, 1H),7.29-7.37 (m, 2H), 7.20 (d, J=6.60 Hz, 1H), 7.12-7.16 (m, 1H), 7.08 (dt,J=8.71, 1.15 Hz, 1H), 4.30-4.45 (m, 2H), 4.11-4.28 (m, 3H), 3.98-4.07(m, 2H), 3.42-3.63 (m, 6H), 3.34 (s, 3H), 1.48-1.59 (m, 2H), 1.22-1.36(m, 30H), 0.89 (t, J=7 Hz, 3H). MS (EI): 704.52 (M+H)⁺, 726.45 (M+Na)⁺.

Example 13. Preparation of benzyl hexadecyloxypropyl9-[2-(phosphonomethoxy)ethyl]guanine (Cmpd 25, Bn-HDP-PMEG)

To a solution of hexadecyloxypropyl9-[2-(phosphonomethoxy)propyl]guanine (HDP PMEG, 0.28 g, 0.49 mmol)[prepared according to: Valiaeva, N. et al., Antiviral Research, 2006,72:10-19], (benzotriazol-1-yloxy)-tripyrrolidinophosphoniumhexafluorophosphate (PYBOP®, 0.39 g, 0.74 mmol), and benzyl alcohol(0.10 ml, 0.74 mmol) in dry N,N-DMF, was added diisopropylethylamine(DIEA, 0.35 ml, 2.0 mmol). The mixture was stirred at room temperaturefor 30 min. The mixture was concentrated under vacuum. The resultingresidue was dissolved in ethyl acetate (50 ml) and then washed withsaturated sodium bicarbonate (2×10 ml). The ethyl acetate layer wasevaporated, and the crude product was purified by flash columnchromatography on silica gel using CH₂Cl₂/MeOH (0-5%) to give 0.03 g(10%) of compound 25 as a powdery white solid. ¹H NMR(CDCl₃/methanol-d₄) δ: 7.62 (s, 1H), 7.30-7.44 (m, 5H), 5.07 (dd,J=8.98, 2.02 Hz, 2H), 4.05-4.24 (m, 4H), 3.83 (m, 4H), 3.31-3.42 (m,4H), 1.87 (m, 2H), 1.54 (m, 2H), 1.17-1.38 (m, 26H), 0.86-0.91 (m, 3H).MS (EI): 662.46 (M+H)⁺, 684.46 (M+Na)⁺.

Example 14. Preparation of benzyl octadecyloxyethyl9-(R)-[2-(phosphonomethoxy)propyl]adenine (Cmpd 74, Bn-ODE-(R)-PMPA)

To a solution of octadecyloxyethyl 9-[2-(phosphonomethoxy)propyl]adenine(ODE-(R)-PMPA, 0.30 g, 0.51 mmol) [prepared as described in: Painter, Get al. Antimicrobial Agents and Chemotherapy, 2007, 51:3505-3509],(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 0.40 g, 0.77 mmol), and benzyl alcohol (0.08 ml, 0.77 mmol) indry N,N-DMF, was added diisopropylethylamine (DIEA, 0.35 ml, 2.0 mmol).The mixture was stirred at room temperature for 30 min, and then thesolvent was evaporated under vacuum. The resulting residue was dissolvedin ethyl acetate (50 ml) and washed with saturated NaHCO₃ (2×10 ml). Theethyl acetate layer was evaporated, and the crude product was purifiedby flash column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%) togive 0.24 g (70%) of compound 74. ¹H NMR (400 MHz, CDCl₃+methanol-d₄) δppm 8.24 (s, 1H), 8.03 (d, J=4.40 Hz, 1H), 7.30-7.42 (m, 5H), 4.99-5.14(m, 2H), 4.35 (d, J=14.66 Hz, 1H), 4.07-4.20 (m, 3H), 3.92 (ddd,J=13.75, 8.98, 4.77 Hz, 2H), 3.65-3.73 (m, 1H), 3.50-3.61 (m, 2H),3.38-3.47 (m, 2H), 1.49-1.61 (m, 2H), 1.27 (m, 30H), 1.21 (d, J=6.23 Hz,3H), 0.09 (t, J=8.00 Hz, 3H). MS (EI): 674.48 (M+H)⁺, 693.46 (M+Na)⁺.

Example 15. Preparation of phenyl octadecyloxyethyl9-(R)-[2-(phosphonomethoxy)propyl]adenine (Cmpd 94, Ph-ODE-(R)-PMPA)

To a solution of octadecyloxyethyl 9-[2-(phosphonomethoxy)propyl]adenine(ODE PMPA, 0.30 g, 0.51 mmol) [prepared as described in: Painter, G etal. Antimicrobial Agents and Chemotherapy, 2007, 51:3505-3509],(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 0.40 g, 0.77 mmol), and phenol (0.072 g, 0.77 mmol) in dryN,N-DMF, was added diisopropylethylamine (DIEA, 0.35 ml, 2.0 mmol). Themixture was stirred at room temperature for 30 min, and then the solventwas evaporated under vacuum. The residue was dissolved in ethyl acetate(50 ml), and washed with saturated sodium bicarbonate solution (2×10ml). The ethyl acetate layer was evaporated, and then the crude productwas purified by column chromatography on silica gel using CH₂Cl₂/MeOH(0-5%) to afford 0.25 g (75%) of compound 94. ¹H NMR (400 MHz,CDCl₃+methanol-d₄) δ ppm 8.24 (d, J=3.30 Hz, 1H), 8.05 (d, J=6.23 Hz,1H), 7.29-7.37 (m, 2H), 7.17-7.24 (m, 1H), 7.05-7.15 (m, 2H), 4.37 (d,J=1.47 Hz, 1H), 4.04-4.31 (m, 4H), 3.94-4.03 (m, 1H), 3.86 (dd, J=9.53,1.10 Hz, 1H), 3.60 (d, J=4.03 Hz, 2H), 3.38-3.47 (m, 2H), 1.48-1.60 (m,2H), 1.21-1.35 (m, 33H), 0.89 (t, J=8.00 Hz, 3H). MS (EI): 660.47(M+H)⁺, 682.41 (M+Na)⁺.

Example 16. Preparation of benzyl octadecyloxyethyl9-(R)-[2-(phosphonomethoxy)propyl] guanine (Cmpd 73, Bn-ODE-(R)-PMPG)

To a solution of octadecyloxyethyl9-(R)-[2-(phosphonomethoxy)propyl]guanine (Bn-ODE-(R)-PMPG, 180 mg, 0.3mmol) [prepared as described in: Painter, G et al. Antimicrobial Agentsand Chemotherapy, 2007, 51:3505-3509],(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 312 mg, 0.6 mmol), and benzyl alcohol (97 mg, 0.9 mmol) in dryN,N-DMF (30 ml), was added diisopropylethylamine (DIEA, 77 mg, 0.6mmol). The mixture was stirred at room temperature for 30 min, and thenthe solvent was evaporated under vacuum. The residue was dissolved inethyl acetate (50 ml), and washed with saturated sodium bicarbonatesolution (2×10 ml). The ethyl acetate layer was evaporated, and then thecrude product was purified by column chromatography on silica gel usingCH₂Cl₂/MeOH (0-5%) to afford 60 mg (29%) of compound 73. ¹H NMR (400MHz, CDCl3+methanol-d₄) δ ppm 7.82 (d, J=5.50 Hz, 1H), 7.75 (d, J=7.33Hz, 1H), 7.43-7.53 (m, 2H), 7.33-7.43 (m, 3H), 5.01-5.17 (m, 1H),4.07-4.18 (m, 2H), 3.82-4.03 (m, 2H), 3.69-3.81 (m, 1H), 3.51-3.64 (m,1H), 3.44 (d, J=7.70 Hz, 1H), 3.36 (dt, J=3.30, 1.65 Hz, 3H), 1.54 (m,2H), 1.21-1.35 (m, 30H), 1.18 (dd, J=6.23, 2.57 Hz, 3H), 0.88 (t, J=8.00Hz, 3H). MS (EI): 690.49 (M+H)⁺, 712.48 (M+Na)⁺.

Example 17. Preparation of benzyl octadecyloxyethyl(S)-9-[3-fluoro-2-(phosphonomethoxy)propyl]guanine (Cmpd 289, BnODE-(S)-FPMPG)

9-(S)-[3-Fluoro-2-(phosphonomethoxy)propyl] guanine [(S)-FPMPG, 0.32 g,1.05 mmol) [prepared as described in: Jindiich, J. et al., Collect.Czech. Chem. Commun., 1993, 58:1645-1667], was esterified withoctadecyloxyethanol (0.33 g, 1.05 mmol) usingN,N-dicyclohexylcarbodiimide (DCC, 0.43 g, 2.1 mmol) in dry N,N-DMF (25ml) at 50° C. overnight. Octadecyloxyethyl(S)-9-[3-fluoro-2-(phosphonomethoxy)propyl] guanine (ODE(S)-FPMPG) wasisolated by column chromatography to give 0.11 g (17%) of the product.¹H NMR (CDCl₃/methanol-d₄), δ 8.18 (s, 1H); 4.50-4.75 (m, 2H); 4.43-4.49(m, 1H); 4.07-4.16 (m, 1H); 3.98-4.17 (m, 2H); 3.84-3.72 (m, 1H);3.56-3.60 (m, 2H); 3.42-3.48 (m, 2H); 3.35-3.37 (m, 1H); 1.52-1.60 (m,2H); 1.20-1.34 (m, 30H); 0.88 (t, J=7 Hz, 3H). MS (EI): 600.30 (M−H)⁻.

A stirred mixture of ODE-(S)-FPMPG (0.11 g, 0.18 mmol), benzyl alcohol(0.06 ml, 0.54 mmol) and(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 0.28 g, 0.54 mmol) in dry DMF was treated withdiisopropylethylamine (DIEA, 0.25 ml, 1.44 mmol) for 4 hours at roomtemperature. The solvent was evaporated under vacuum. The residue wasdissolved in ethyl acetate (50 ml), and washed with saturated sodiumbicarbonate solution (2×10 ml). The ethyl acetate layer was evaporated,and then the crude product was purified by column chromatography onsilica gel using CH₂Cl₂/MeOH (0-5%) to afford 90 mg (71%) of compound289. ¹H NMR (400 MHz, CDCl₃+methanol-d₄) δ ppm 7.77 (s, 1H), 7.46-7.54(m, 2H), 7.34-7.42 (m, 3H), 5.04-5.17 (m, 1H), 4.42-4.52 (m, 2H),4.19-4.38 (m, 2H), 4.09-4.19 (m, 2H), 3.88-4.06 (m, 2H), 3.64-3.73 (m,1H), 3.55-3.64 (m, 1H), 3.41-3.50 (m, 1H), 3.18 (d, J=7.33 Hz, 1H),1.49-1.60 (m, 2H), 1.21-1.35 (m, 30H), 0.88 (t, J=7 Hz, 3H). MS (EI):708.50 (M−H)⁻, 730.52 (M+Na)⁺.

Example 18. Preparation of naphthyl octadecyloxyethyl9-(S)-[3-methoxy-2-(phosphonomethoxy)propyl]adenine (Cmpd 398,Npt-ODE-(S)-MPMPA)

To a solution of octadecyloxyethyl 9-[3-methoxy-2-(phosphonomethoxy)propyl]adenine (ODE MPMPA, 0.30 g, 0.49 mmol) [prepared as described in:Valiaeva, N. et al. Bioorganic & Medicinal Chemistry, 2011, 19:4616-4625], (benzotriazol-1-yloxy)-tripyrrolidinophosphoniumhexafluorophosphate (PYBOP®, 0.38 g, 0.73 mmol), and 1-naphthol (0.11 g,0.73 mmol) in dry N,N-DMF, was added diisopropylethylamine (DIEA, 0.35ml, 2.0 mmol). The mixture was stirred at room temperature overnight,and then the solvent was evaporated under vacuum. The residue wasdissolved in ethyl acetate (50 ml) and washed with saturated sodiumbicarbonate (2×10 ml). The ethyl acetate layer was evaporated, and thenthe crude product was purified by column chromatography on silica gelusing CH₂Cl₂/MeOH (0-5%) to yield 0.20 g (56%) of compound 398 as an offwhite solid. ¹H NMR (400 MHz, CDCl₃+methanol-d₄) δ ppm 8.18 (d, J=8.07Hz, 1H), 8.02-8.11 (m, 1H), 7.94 (s, 1H), 7.86-7.90 (m, 1H), 7.69-7.74(m, 1H), 7.48-7.57 (m, 2H), 7.34-7.43 (m, 2H), 4.38-4.46 (m, 1H),4.26-4.37 (m, 3H), 4.09-4.24 (m, 2H), 3.99-4.09 (m, 1H), 3.59 (t, J=4.58Hz, 1H), 3.47-3.56 (m, 2H), 3.30-3.45 (m, 5H), 1.49 (d, J=6.60 Hz, 2H),1.19-1.34 (m, 30H), 0.85-0.93 (t, J=7 Hz, 3H). MS (EI): 740.54 (M+H)⁺,762.52 (M+Na)⁺.

Example 19. Preparation of naphthyl octadecyloxyethyl9-[2-(phosphonomethoxy) ethyl]guanine (Cmpd 361, Npt-ODE-PMEG)

To a solution of octadecyloxyethyl 9-[2-(phosphonomethoxy)ethyl]guanine(ODE PMEG, 0.29 g, 0.50 mmol) [prepared according to: Valiaeva, N. etal. Antiviral Research 2006, 72: 10-19],(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 0.39 g, 0.75 mmol), and 1-naphthol (0.11 g, 0.75 mmol) in dryN,N-DMF, was added diisopropylethylamine (DIEA, 0.35 ml, 2.0 mmol). Themixture was stirred at room temperature overnight and then the solventwas evaporated under vacuum. The residue was dissolved in ethyl acetate(50 ml) and then washed with saturated sodium bicarbonate (2×10 ml). Theethyl acetate layer was evaporated. The crude product was purified byflash column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%) togive 0.23 g (65%) of compound 361. ¹H NMR (CDCl₃/methanol-d₄) δ: ¹H NMR(400 MHz, CDCl₃+methanol-d₄) δ ppm 8.07-8.12 (m, 1H), 7.87 (dd, J=5.87,3.30 Hz, 1H), 7.71 (d, J=5.87 Hz, 1H), 7.59 (d, J=4.40 Hz, 1H),7.52-7.56 (m, 1H), 7.39-7.43 (m, 1H), 4.30 (ddd, J=8.62, 5.68, 3.30 Hz,2H), 4.16-4.21 (m, 2H), 4.14 (d, J=8.07 Hz, 2H), 3.64-3.72 (m, 2H),3.56-3.61 (m, 1H), 3.38 (d, J=4.77 Hz, 1H), 3.19 (q, J=7.45 Hz, 2H),1.45-1.54 (m, 2H), 1.15-1.35 (m, 30H), 0.88 (t, J=7 Hz, 3H). MS (EI):712.49 (M+H)⁺, 734.41 (M+Na)⁺.

Example 20. Preparation of benzyl octadecyloxyethyl9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]uracil (Cmpd 221,Bn-ODE-(S)-HPMPU)

To a solution of benzyl9-[3-trityloxy-2-(phosphonomethoxy)propyl]-4-methoxy-uracil (0.1 g, 0.15mmol), (benzotriazol-1-yloxy)-tripyrrolidinophosphoniumhexafluorophosphate (PYBOP®, 0.11 g, 0.20 mmol), and octadecyloxyethanol(0.06 g, 0.20 mmol) in dry N,N-DMF was added diisopropylethylamine(DIEA, 0.03 ml, 0.20 mmol). The mixture was stirred at room temperatureovernight. The solvent was evaporated under vacuum. The residue wasdissolved in ethyl acetate (50 ml), washed with saturated sodiumbicarbonate (2×10 ml), and then the ethyl acetate layer was concentratedunder vacuum. The resulting crude product was purified by flash columnchromatography on silica gel using CH₂Cl₂/MeOH (0-5%) to give 0.024 g(17%) of benzyl octadecyloxyethyl9-[3-trityloxy-2-(phosphonomethoxy)propyl]-4-methoxyuracil ¹H NMR (400MHz, CDCl₃+methanol) δ ppm 7.56 (d, J=5.50 Hz, 1H), 7.16-7.51 (m, 15H),5.46 (d, J=5.50 Hz, 1H), 5.10 (d, J=8.80 Hz, 2H), 4.03-4.21 (m, 2H),3.86-3.99 (m, 1H), 3.65-3.85 (m, 2H), 3.37-3.60 (m, 4H), 3.25 (s, 3H),3.12 (m, 1H), 1.42-1.62 (m, 2H), 1.-5-1.38 (m, 30H), 0.88 (t, J=6.97 Hz,3H). MS (EI): 945.66 (M+Na)⁺

The protected intermediate was then stirred in 80% aq acetic acidovernight at 50° C. The solvent was then evaporated under vacuum, andthe residue was purified by flash column chromatography to give 0.01 g(59%) of compound 221. MS (EI): 667.54 (M+H)⁺, 689.56 (M+Na)⁺.

Example 21. Preparation of ethyl octadecyloxyethyl9-(S)-[3-methoxy-2-(phosphonomethoxy)propyl]adenine (Cmpd 182,Et-ODE-(S)-MPMPA)

To a solution of octadecyloxyethyl 9-(S)-[3-methoxy-2-(phosphonomethoxy)propyl]-adenine (ODE-(S)-MPMPA, 0.30 g, 0.49 mmol) [prepared asdescribed in: Valiaeva, N. et al. Bioorganic & Medicinal Chemistry,2011, 19:4616-4625], (benzotriazol-1-yloxy)-tripyrrolidinophosphoniumhexafluorophosphate, (PYBOP®, 0.38 g, 0.73 mmol), in ethanol (25 ml),was added diisopropylethylamine (DIEA, 0.35 ml, 2.0 mmol). The mixturewas stirred at room temperature overnight. The solvent was thenevaporated under vacuum. The residue was dissolved in ethyl acetate (50ml), and then washed with saturated sodium bicarbonate (2×10 ml). Ethylacetate was evaporated, and the residue was purified by flash columnchromatography on silica gel using CH₂Cl₂/MeOH (0-5%) to give 0.26 g(84%) of compound 182 as a white solid. ¹H NMR (400 MHz,CDCl₃+methanol-d₄) δ ppm 8.26 (s, 1H), 8.08 (d, J=2.20 Hz, 1H),4.72-4.74 (m, 1H), 4.62-64 (m, 1H), 4.44-4.50 (m, 1H), 4.28-4.35 (m,1H), 4.10-4.18 (m, 2H), 4.03-4.10 (m, 2H), 3.81-3.89 (m, 1H), 3.53-3.64(m, 3H), 3.42-3.52 (m, 3H), 3.40 (s, 3H), 1.56 (m, 2H), 1.19-1.37 (m,33H), 0.89 (t, J=7.20 Hz, 3H). MS (EI): 642.69 (M+H)⁺, 664.61 (M+Na)⁺.

Example 22. Preparation of benzyl octadecyloxyethyl9-[3-methoxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (Cmpd 150,Bn-ODE(S)-MPMPDAP)

To a solution of octadecyloxyethyl 9-(S)-[3-methoxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (ODE-(S)-MPMP DAP, 0.20 g, 0.32 mmol)[prepared as described in: Valiaeva, N. et al. Bioorganic & MedicinalChemistry, 2011, 19:4616-4625],((benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®) (0.21 g, 0.40 mmol), and benzyl alcohol (0.04 ml, 0.40 mmol) indry N,N-DMF, was added diisopropylethylamine (DIEA, 0.07 ml, 0.40 mmol).The mixture was stirred at room temperature overnight, and then thesolvent was evaporated under vacuum. The residue was dissolved in ethylacetate (50 ml), and then washed with saturated sodium bicarbonate (2×10ml). The ethyl acetate layer was evaporated, and then the residue waspurified by flash column chromatography on silica gel using CH₂Cl₂/MeOH(0-5%) to give 0.12 g (54%) of compound 150. ¹H NMR (400 MHz,CDCl₃+methanol-d₄) δ ppm 7.63-7.68 (m, 1H), 7.31-7.43 (m, 5H), 5.02-5.13(m, 2H), 4.59 (s, 1H), 4.50 (s, 1H), 4.23 (d, J=3.67 Hz, 1H), 3.99-4.15(m, 3H), 3.84-3.92 (m, 2H), 3.39-3.56 (m, 5H), 3.36 (s, 3H), 1.49-1.58(m, 2H), 1.17-1.35 (m, 30H), 0.89 (t, J=6.6 Hz, 3H). MS (EI): 719.62(M+H)⁺, 741.56 (M+Na)⁺.

Example 23. Antiproliferative Activity of Nucleoside PhosphonatesDiesters in Normal Human Fibroblasts and in Human Cervical Cancer LinesIn Vitro

Method. Compounds at a range of concentrations were incubated withnormal fibroblasts or human cervical cancer cell lines in monolayerculture and after 4 days, viable cell number was determined by neutralred reduction as previously described (Valiaeva N, et al., Chemotherapy,2010, 56(1):54-9). Cell lines were obtained from American Type CultureCollection. The results were plotted and the concentration which reducedneutral red levels by 50% (CC₅₀) was determined in triplicate. Althoughviral replication is no longer occurring in the human cervical cancercell lines, Caski cells were transformed by HPV-16 and Hela cells weretransformed by HPV-18.

Results.

As tabulated in Table 11 following, these results demonstrate thatcompounds described herein were 23.6 fold (e.g., Cmpd 219) to 3,750 fold(e.g., Cmpd 1) more effective in reducing viable cell number in thecervical cancer lines than in normal, non-transformed human fibroblasts.

TABLE 11 Antiproliferative activity of nucleoside phosphonate diestersin normal human fibroblasts and in human cervical cancer lines in vitroCytotoxic concentration 50% (CC₅₀) μM Normal human fibroblasts CaskiHela Compound # (HFF) (HPV-16) (HPV-18) 219 52 2.0 2.2 218 5.2 0.0550.029 1 15 0.004 0.009

Example 24. Antiproliferative Activity of Compounds on Human T CellLeukemia Cells (MT-2)

Method of cytotoxicity determination. MT-2 cells were incubated withdrug for 72 hrs and harvested. Flow count beads (Beckman Coulter, Miami,Fla.) were added to the cell suspension followed by propidium iodidestaining and analysis using flow cytometer and the 50% cytotoxicconcentration (CC₅₀) was calculated from the cell counts and viability.

Results.

Compounds disclosed herein are effective antiproliferative agents inhuman T cell leukemia (MT-2) cells (Table 12).

TABLE 12 Antiproliferative activity in human MT-2 leukemic cells invitro CC₅₀, 50% Cytotoxic concentration μMMT2 Compound # cells T cellleukemia 1 0.036 ± 0.04 1a <0.01  1b <0.01  2 <0.010

Example 25. Anti-HIV Activity

Method HIV Antiviral Assays.

MT-2 cells were maintained in RPMI 1640 supplemented with 10% FBS, 10 mMHEPES buffer, 50 IU of penicillin/ml, and 50 μg of streptomycin/ml. Theantiviral activity of each compound was determined by inoculating MT-2cells with HIV-1_(LAI) at a multiplicity of infection (MOI) of 0.001TCID₅₀/cell, followed by incubation in the presence of threefold serialdrug dilutions (three wells per dilution). Four days after infection,culture supernatants were harvested, lysed with 0.5% Triton X-100, andassayed for p24 antigen concentration using a commercial ELISA assay(Perkin Elmer Life Sciences, Boston, Mass.). The antiviral activity ofeach compound is expressed as the EC₅₀, which is the concentrationrequired to inhibit p24 antigen production by 50%.

Method Cytotoxicity Determination.

MT-2 cells were incubated with drug for 72 hrs and harvested. Flow countbeads (Beckman Coulter, Miami, Fla.) were added to the cell suspensionfollowed by propidium iodide staining and analysis using flow cytometerand the 50% cytotoxic concentration (CC₅₀) was calculated from the cellcounts and viability.

Results.

Table 13 shows that compounds disclosed herein have considerableantiviral activity against HIV-1 and exhibit selectivity.

TABLE 13 Antiviral activity in HIV-1 infected human lymphoblasticleukemia cells HIV ANTIVIRAL ACTIVITY IN MT-2 CELLS EC₅₀, CC₅₀,Selectivity Compound # μM μM Index 1 <1 × 10⁻⁵   0.036 ±0.04     >3600    2 <1 × 10⁻⁵   <1 × 10⁻²   — 218 0.13 ± 0.14 (3) 2.3 ±1.6 (3)  17.7 219 2.7 ± 2.1 (3) 18 ± 3.6 (3) 6.7 230 0.05 ± 0.03 (3) 19± 2.6 (3) 380 231 2.2 ± 2.1 (3) 22 ± 3.0 (3) 10 EC₅₀, effective dose50%; CC₅₀, cytotoxic dose 50%, selectivity index CC₅₀/EC₅₀. Assay: p24reduction.

Example 26. Antiviral Effect of ANP Diesters in HFF Cells Infected withHSV-2

Method.

Primary low passage human foreskin fibroblast (HFF) cells in 96-wellplates were infected at an MOI of 0.01 PFU/cell with the G strain ofherpes simplex virus type 2 and incubated for 3 days. Media was thenaspirated and cell monolayers were stained with crystal violet andrinsed with distilled water. Crystal violet associated with the cellswas then quantified in a spectrophotometer and the concentration of thecompound that was sufficient to reduce virus replication by 50% (EC₅₀)was calculated. Cytotoxicity was measured in parallel by similar methodsto yield the concentration that reduced cell number by 50% (CC₅₀).

Results.

Results are tabulated in Table 14 following.

TABLE 14 Antiviral Effect of ANP diesters in HFF cells infected withHSV-2 EC₅₀, CC₅₀, Selectivity Compound # μM μM Index 219 0.10 13.1 131218 0.04 6.91 173 231 0.80 34.8 43.5 230 0.71 37.1 52.2 221 3.8 10 2.6

Example 27. Effect of Oral Octadecyloxyethyl-benzyl-(ODE-bn-) AcyclicNucleoside Phosphonate Diesters and ODE-Monoesters of Acyclic NucleosidePhosphonates on Body Weight in Balb-c Mice

Method.

Compounds were administered at the indicated doses by oral gavage dailyfor 5 days. Weights measured before and on day 6 after 5 doses.

Results.

As tabulated in Table 15 following, these results demonstrate thatODE-monoesters of Cidofovir (CDV) and PMEG lost 14.7% and 19.1% of bodyweight, respectively, which was highly statistically significant versusday zero (p=0.0007 and p<0.001). However, oral ODE-benzyl diesters ofthe CDV and PMEG nucleoside phosphonates exhibited no statisticallysignificant effects (“ns”) on body weight compared with the unmodifiedcompounds.

TABLE 15 Effect of oral Octadecyloxyethyl-benzyl-(ODE-bn-) acyclicphosphonate diesters and Octadecyloxyethyl-monoesters of acyclicnucleoside phosphonates on body weight in Balb-c Mice p value, CompoundDose Day 0 Day 6 0 vs 6 ODE-CDV 20 mg/kg/day 19.88 ± 0.55 (6)   16.96 ±01.38 (6) 0.0007 ODE-bn-CDV 20 mg/kg/day 19.03 ± 1.16 (6)  19.27 ± 1.32(6) ns (Cmpd 219) ODE-PMEG  4 mg/kg/day 19.17 ± 0.581 (3)   15.5 ± 0.514(3) <0.001  ODE-bn-PMEG  4 mg/kg/day 18.63 ± 0.728 (3) 18.42 ± 1.00 (3)ns (Cmpd 1)

Example 28. Antiviral Effect of ANP Diesters in Cells Infected withHuman Cytomegalovirus (AD169)

Method. Primary low passage human foreskin fibroblast (HFF) cells in96-well plates were infected at an MOI of 0.01 PFU/cell with the AD169strain of human cytomegalovirus and incubated for 14 days. Media wasthen aspirated and cell monolayers were stained with crystal violet andrinsed with distilled water. Crystal violet associated with the cellswas then quantified in a spectrophotometer and the concentration of thecompound that was sufficient to reduce virus replication by 50% (EC₅₀)was calculated. Cytotoxicity was measured in parallel by similar methodsto yield the concentration that reduced cell number by 50% (CC₅₀).

Results.

Results are tabulated in Table 16 following.

TABLE 16 Antiviral Effect of ANP diesters in cells infected with humancytomegalovirus (AD169) EC₅₀, CC₅₀, Selectivity Compound # μM μM Index219 <0.03 84.2 >2807 218 <0.03 7.49 >250 231 <0.03 19.0 >633 230 <0.033.72 >124 1 <0.03 51.5 >1717 2  0.11 18.3 166

Example 29. Antiviral Effect of ANP Diesters in Cells Infected withVaccinia Virus (Copenhagen)

Method: Primary low passage human foreskin fibroblast (HFF) cells in96-well plates were infected at an MOI of 0.01 PFU/cell with theCopenhagen strain of vaccinia virus and incubated for 7 days. Media wasthen aspirated and cell monolayers were stained with crystal violet andrinsed with distilled water. Crystal violet associated with the cellswas then quantified in a spectrophotometer and the concentration of thecompound that was sufficient to reduce virus replication by 50% (EC₅₀)was calculated. Cytotoxicity was measured in parallel by similar methodsto yield the concentration that reduced cell number by 50% (CC₅₀).

Results.

Results are tabulated in Table 17 following.

TABLE 17 Antiviral Effect of ANP diesters in cells infected withvaccinia virus (Copenhagen) EC₅₀, CC₅₀, Selectivity Compound # μM μMIndex 219 0.09 >100 >1110 218 <0.03 >100 >3330 231 0.23 >100 >435 2300.06 97.5 1625

Example 30. Antiviral Effect of ANP Diesters in Cells Infected BK Virus(Gardner Strain)

Method:

Primary low passage human foreskin fibroblast (HFF) cells in 96-wellplates were infected at an MOI of 0.01 PFU/cell and incubated for 14days. Media was then aspirated and total DNA was isolated and genomecopy number was quantified by qPCR using the primers 5′-AGT GGA TGG GCAGCC TAT GTA-3′ (SEQ ID NO:1), 5′-TCA TAT CTG GGT CCC CTG GA-3′ (SEQ IDNO:2) and probe 5′-6-FAM AGG TAG AAG AGG TTA GGG TGT TTG ATG GCA CAGTAMRA-3′(SEQ ID NO:3). In a parallel experiment in uninfected cellscytotoxicity was determined by CELLTITER-GLO® find the concentrationthat reduced cell number by 50% (CC₅₀).

Results.

Results are tabulated in Table 18 following.

TABLE 18 Antiviral Effect of ANP diesters in cells infected BK virus(Gardner strain) EC₅₀, CC₅₀, Selectivity Compound # μM μM Index 219<0.03 6.54 >218 218 <0.03 2.80 >93 231 <0.03 13.29 >443 230  0.06 19.61327 1 <0.03 3.06 >102 2 <0.03 7.14 >238

Example 31. Antiviral Effect of ANP Diesters in HFF Cells Infected withHSV-1 (E-377)

Method.

Primary low passage human foreskin fibroblast (HFF) cells in 96-wellplates were infected at an MOI of 0.01 PFU/cell with the E377 strain ofherpes simplex virus type 1 and incubated for 3 days. Media was thenaspirated and cell monolayers were stained with crystal violet andrinsed with distilled water. Crystal violet associated with the cellswas then quantified in a spectrophotometer and the concentration of thecompound that was sufficient to reduce virus replication by 50% (EC₅₀)was calculated. Cytotoxicity was measured in parallel by similar methodsto yield the concentration that reduced cell number by 50% (CC₅₀).

Results.

Results are tabulated in Table 19 following.

TABLE 19 Antiviral Effect of ANP diesters in HFF cells infected withHSV-1 (E-377) EC₅₀, CC₅₀, Selectivity Compound # μM μM Index 219 1.2519.3 15.4 218 0.92 14.5 15.8 231 1.40 88.3 63 230 2.77 82.2 30 11.08 >100 >93 2 >4.0 16.6 <4.2

Example 32. Antiviral Effect of ANP Diesters in HPV-11 Infected HEK 293Cells

Method.

An origin-containing plasmid was co-transfected with HPV-11 E1 and E2protein expression vectors into HEK 293 cells. At 4 hrpost-transfection, cells were treated with compound dilutions and thecells were incubated for 48 hr. Replication of the virus origin wasdetected with DpnI and exonuclease III to remove unreplicated inputbacterial plasmid DNA. Remaining replicated DNA was quantified by qPCR.Toxicity was determined by trypan blue exclusion.

Results.

Results are tabulated in Table 20 following.

TABLE 20 Antiviral effect of ANP diesters in HPV-11 infected HEK 293cells EC₅₀, CC₅₀, Selectivity Compound # μM μM Index  1 0.49 >100 >204  1a [1.06, EC₉₀] — —   1b [1.16, EC₉₀] — — 218 0.77 >100 >370  20.27 >100 >130 219 2.04 >10 >4.9 230 0.56 >10 >17.9 231 1.56 >10 >6.41** EC₉₀ is the concentration required to reduce viral replication by90%.

Example 33. Antiviral Effect of ANP Diesters in HPV-16 Infected HEK 293Cells

Method. An origin-containing plasmid was co-transfected with HPV-16 E1and E2 protein expression vectors into HEK 293 cells. At 4 hrpost-transfection, cells were treated with compound dilutions and thecells were incubated for 48 hr. Replication of the virus origin wasdetected with DpnI and exonuclease III to remove unreplicated inputbacterial plasmid DNA. Remaining replicated DNA was quantified by qPCR.Toxicity was determined by trypan blue exclusion.

Results.

Results are tabulated in Table 21 following.

TABLE 21 Antiviral effect of ANP diesters in HPV-16 infected HEK 293cells. EC₅₀, CC₅₀, Selectivity Compound # μM μM Index 218 0.24 >10 >41.7219 2.23 >10 >4.48 1 0.20 >10 >50 19 5.27 >10 >1.9 2 0.99 >10 >10.1

Example 34. Antiviral Effect of ANP Diesters in HPV-18 Infected PrimaryHuman Keratinocyte Rafts

Method.

Primary human keratinocytes (PHKs) were transfected with an HPV-18genomic plasmid containing G418 resistance gene which was generated byCre-loxP-mediated excision recombination. After a 4 day selection withG418, the surviving cells were cultured for 2-3 day and used to developinto raft cultures where the PHK cells stratify and differentiate into asquamous epithelium in 10 or more days. HPV-18 viral DNA usuallyamplifies between 10-14 days after the raft cultures are lifted to theair-medium interface. Efficacy and toxicity of the test compounds weredetermined at three concentrations added to the media from day 6 or 8until day 14. Medium is changed every other day. Prior to harvest, BrdUis added to the medium at 100 μg/ml to document host cell DNAreplication. One set of raft cultures (with or without test compounds)is harvested for quantitative real time PCR (qPCR) to determine the copynumber of HPV-18 DNA/cell. Another set of the raft cultures are fixed informalin, embedded in paraffin and toxicity is determined by histology.Additional sections are subjected to in situ hybridization to localizeviral DNA amplification and BrdU incorporation which denotes host DNAreplication in basal and suprabasal strata.

Results.

Results are tabulated in Table 22 following.

TABLE 22 Antiviral effect of ANP diesters in HPV-18 infected primaryhuman keratinocyte rafts EC₅₀, CC₅₀, Selectivity Compound # μM μM Index218 0.25 >10 >39 219 1.06 >10 >9.4 1 0.21  10 48

Example 35. Antiviral Effect of ANP Diesters in JC Virus (MAD-1)Infected COS7 Cells

Method.

COS7 cells in 96-well plates were infected at an MOI of 0.01 PFU/cellwith the MAD-1 strain of JC virus and incubated for 7 days. Media wasthen aspirated and total DNA was isolated and genome copy number wasquantified by qPCR using primers 5′-CTG GTC ATG TGG ATG CTG TCA-3′ (SEQID NO:4) and 5′-GCC AGC AGG CTG TTG ATA CTG-3′ (SEQ ID NO:5) and probe5′-6-FAM-CCC TTT GTT TGG CTG CT-TAMRA-3 (SEQ ID NO:6) together with theplasmid pMP508 to provide a standard curve for quantitation. In aparallel experiment in uninfected cells, cytotoxicity was determined byCELLTITER-GLO® to find the concentration that reduced cell number by 50%(CC₅₀).

Results.

Results are tabulated in Table 23 following.

TABLE 23 Antiviral effect of ANP diesters in JC virus (MAD-1) infectedCOS7 cells EC₅₀, CC₅₀, Selectivity Compound # μM μM Index 1 0.07 63.8911 2 >4 10.6 <2.7 218 >4 10.2 <2.6 219 >4 12.8 <3.2 230 >4 18.4 <4.6231 >20 62.6 <3

Example 36. Antiviral Effect of ANP Diesters in HIV-1_(92US727) InfectedHuman Peripheral Blood Monocytes

Method.

Human peripheral blood monocyte (PBMC) based anti-HIV assays wereperformed as previously described (K. M. Watson, et al., 2008,Antimicrob Agents Chemother. 52:2787). Briefly, PHA-stimulated PBMCscultured in the presence of IL-2 were suspended at 1×10⁶ cells/mL andwere added to a 96-well round-bottom plate. Serially diluted testmaterials were added to the plate in triplicate followed by theappropriate pre-titered strain of HIV. The culture was incubated for 7days at 37° C./5% CO₂. Following the incubation, supernatants werecollected for analysis of virus replication by supernatant reversetranscriptase activity and cells analyzed for viability by tetrazoliumdye XTT reduction(2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazoliumhydroxide). All the assays were carried out in triplicate. MicrosoftExcel 2007 was used to analyze and graph data. The percent reduction invirus replication compared to the untreated virus controls wascalculated for each compound. The percent cell control value wascalculated for each compound comparing the drug treated uninfected cellsto the uninfected cells in medium alone.

Results.

Results are tabulated in Table 24 following.

TABLE 24 Antiviral effect of ANP diesters in HIV-1_(92US727) infectedhuman peripheral blood monocytes EC₅₀, CC₅₀, Selectivity Compound # μMμM Index 218 <0.010 0.23 >23.0 230 <0.10 0.55 >25.5 219 <0.10 2.87 >28.7231 <0.30 19.0 >63.3 2 <0.010 11.0 >1100 1 <0.010 0.04 >4.0 19 <0.0030.018 >9.0 25 <0.002 0.25 >125 164 <0.40 15.0 >37.5 146 <0.04 12.5 >31274 <0.005 24.6 >4920 92 <0.005 24.1 >4820 73 <0.005 11.3 >2260

Example 37. Antiviral Effect of ANP Diesters on Hepatitis B VirusReplication in 2.2.15 Cells In Vitro

Method. HBV antiviral assays (Korba & Gerin, Antivir. Res., 1992, 19:55and Iyer, et al., Antivir Agents Chem Chemother., 2004, 48:2199) areconducted using confluent cultures of 2.2.15 cells (genotype ayw;parental cell HepG2) maintained on 96-well flat-bottomed tissue cultureplates. Confluence in this culture system is required for active, highlevels of HBV replication equivalent to that observed inchronically-infected individuals (Sells, et al., J. Virol., 1988,62:2836; Korba & Gerin, Antivir. Res., 1992, 19:55). Cultures aretreated for 7 days. HBV DNA levels in the culture medium (representingHBV virion production) are assessed by quantitative blot hybridization24 hrs. after the last treatment. Cytotoxicity is assessed (A₅₁₀) byuptake of neutral red dye 24 hr. following the last treatment.Lamivudine (LMV) is used as the standard assay control. EC₅₀, EC₉₀ andCC₅₀ values are calculated by linear regression analysis (MS EXCEL®,QUATTROPRO®) using data combined from all treated cultures (Korba &Gerin, 1992, Id.; Okuse, et al., Antivir. Res., 2005, 65:23). Standarddeviations for EC₅₀ and EC₉₀ values are calculated from the standarderrors generated by the regression analyses. EC₅₀ and EC₉₀ are drugconcentrations at which a 2-fold, or a 10-fold depression of HBV DNA(relative to the average levels in untreated cultures), respectively, isobserved. CC₅₀ is the drug concentration at which a 2-fold lower levelof neutral red dye uptake (relative to the average levels in untreatedcultures) is observed.

Results.

Results are tabulated in Table 25 following.

TABLE 25 Antiviral effect of ANP diesters on hepatitis B virusreplication in 2.2.15 cells in vitro. EC₅₀, EC₅₀, Selectivity Compound #μM μM Index 2 0.88 >100 >113 218 0.76 >100 >132 219 0.45 >100 >223 1943.0 >100 >2.33 1 0.44 >100 >226 146 33.0 >100 >3.03 164 0.46 >100 >21674 6.5  64 10 92 7.3  68 9.3 73 34  63 1.9

EMBODIMENTS

A first set of embodiments P1-P7 follows.

Embodiment P1

A compound with structure of Formula (I):

or stereoisomer, salt, hydrate, solvate, or crystalline form thereof,wherein B_(Nuc) is a naturally occurring purine or pyrimidine base, oranalog thereof; L is a lipophilic promoiety, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl, orO-substituted glyceryl having the formula —CH₂CH(OR¹)—CH₂(OR²) (II),wherein R¹ and R² are independently substituted or unsubstituted alkyl,or substituted or unsubstituted aryl; R is substituted or unsubstitutedlower alkyl, substituted or unsubstituted lower heteroalkyl, substitutedor unsubstituted lower cycloalkyl, substituted or unsubstituted lowerheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted lower heteroaryl; and X is hydrogen, substituted orunsubstituted lower alkyl, or substituted or unsubstituted lowerheteroalkyl.

Embodiment P2

A method of treating a viral disease in a subject, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of embodiment P1.

Embodiment P3

A method for treating cancer in a subject, comprising administering to asubject in need thereof a therapeutically effective amount of a compoundof embodiment P1.

Embodiment P4

A method of killing or inhibiting the growth of a transformed cell,comprising contacting a transformed cell with a therapeuticallyeffective amount of a compound of embodiment P1.

Embodiment P5

A method for treating a proliferative disorder in a subject, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of embodiment P1.

Embodiment P6

A pharmaceutical composition comprising a compound according toembodiment P1, and pharmaceutically acceptable excipient.

Embodiment P7

A method for synthesis of a compound with structure of Formula (I)according to Scheme 2:

wherein B_(Nuc) is a naturally occurring purine or pyrimidine base, oranalog thereof; L is a lipophilic promoiety, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl, orO-substituted glyceryl having the formula —CH₂CH(OR¹)—CH₂(OR²) (II),wherein R¹ and R² are independently substituted or unsubstituted alkyl,or substituted or unsubstituted aryl; R is substituted or unsubstitutedlower alkyl, substituted or unsubstituted lower heteroalkyl, substitutedor unsubstituted lower cycloalkyl, substituted or unsubstituted lowerheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted lower heteroaryl; and X is hydrogen, substituted orunsubstituted lower alkyl, or substituted or unsubstituted lowerheteroalkyl; and Y is a leaving group; the method including: 1)contacting a protected nucleoside B_(Nuc) with structure of Formula(2-1) with an ester with structure of Formula (2-2) in the presence of astrong base under conditions suitable to afford a monoester withstructure of Formula (2-3); and 2) reacting said monoester withstructure of Formula (2-3) with L-OH in the presence of a couplingagent, thereby synthesizing a compound with structure of Formula (I).

Further embodiments include the following.

Embodiment 1

A compound of Formula (Ia), or a pharmaceutically acceptable salt,hydrate, solvate or crystalline form thereof:

wherein: B_(Nuc(a)) is a naturally occurring purine, a naturallyoccurring pyrimidine, a non-naturally occurring purine or anon-naturally occurring pyrimidine; L^(a) is an unsubstituted C₁₂₋₂₄alkyl, an unsubstituted C₁₃₋₂₉ heteroalkyl or a substituted glycerylmoiety, wherein the glyceryl moiety is substituted with one or moregroups selected from an unsubstituted C₁₃₋₂₉ alkyl, an unsubstitutedC₁₃₋₂₉ heteroalkyl, a substituted or unsubstituted aryl(C₁₋₆ alkyl), asubstituted or unsubstituted heteroaryl(C₁₋₆ alkyl) and a substituted orunsubstituted heterocycloalkyl(C₁₋₆ alkyl); R^(a) is selected from thegroup consisting of an unsubstituted C₁₋₆ alkyl, a substituted orunsubstituted aryl, a substituted or unsubstituted heteroaryl, asubstituted or unsubstituted heterocycloalkyl, a substituted orunsubstituted aryl(C₁₋₆ alkyl), a substituted or unsubstitutedheteroaryl(C₁₋₆ alkyl) and a substituted or unsubstitutedheterocycloalkyl(C₁₋₆ alkyl); and X^(a) is hydrogen, an unsubstitutedC₁₋₆ alkyl, a halogen substituted C₁₋₆ alkyl, a hydroxy substituted C₁₋₆alkyl or an unsubstituted C₁₋₆ alkoxy.

Embodiment 2

The compound of embodiment 1 wherein X^(a) is hydrogen.

Embodiment 3

The compound of embodiment 1 wherein X^(a) is methyl.

Embodiment 4

The compound of embodiment 1, wherein X^(a) is methoxy.

Embodiment 5

The compound of embodiment 1, wherein X^(a) is a fluoro substituted C₁₋₆alkyl.

Embodiment 6

The compound of embodiment 5, wherein X^(a) is a CH₂F.

Embodiment 7

The compound of embodiment 1, wherein X^(a) is a CH₂OH.

Embodiment 8

The compound of any one of embodiments 1-7, wherein L^(a) is anunsubstituted C₁₃₋₂₉ heteroalkyl.

Embodiment 9

The compound of embodiment 8, wherein L^(a) has the structure—(CH₂)₁₋₆—O—(CH₂)₁₁₋₂₁—CH₃.

Embodiment 10

The compound of embodiment 9, wherein L^(a) has the structure—(CH₂)₂—O—(CH₂)₁₇—CH₃.

Embodiment 11

The compound of embodiment 9, wherein L^(a) has the structure—(CH₂)₃—O—(CH₂)₁₅-CH₃.

Embodiment 12

The compound of embodiment 8, wherein L^(a) has the structure—(CH₂)₁₋₆—O—(CH₂)₁₀₋₂₀—(CHCH₃)—CH₃.

Embodiment 13

The compound of any one of embodiments 1-7, wherein L^(a) is asubstituted glyceryl moiety.

Embodiment 14

The compound of embodiment 13, wherein L^(a) has the structure—(CH₂)—CH(OR^(a1))—(CH₂)—O(CH₂)₁₁₋₂₁—CH₃, wherein R^(a1) is asubstituted or unsubstituted aryl(C₁₋₆ alkyl), a substituted orunsubstituted heteroaryl(C₁₋₆ alkyl) and a substituted or unsubstitutedheterocycloalkyl(C₁₋₆ alkyl).

Embodiment 15

The compound of embodiment 14, wherein L^(a) has the structure

Embodiment 16

The compound of embodiment 1, wherein R^(a) is a substituted orunsubstituted aryl.

Embodiment 17

The compound of embodiment 16, wherein the substituted or unsubstitutedaryl is a substituted or unsubstituted phenyl.

Embodiment 18

The compound of embodiment 16, wherein the substituted or unsubstitutedaryl is a substituted or unsubstituted naphthyl.

Embodiment 19

The compound of embodiment 1, wherein R^(a) is a substituted orunsubstituted aryl(C₁₋₆ alkyl).

Embodiment 20

The compound of embodiment 19, wherein the substituted or unsubstitutedaryl(C₁₋₆ alkyl) is a substituted or unsubstituted benzyl.

Embodiment 21

The compound of embodiment 1, wherein R^(a) is a substituted orunsubstituted heterocycloalkyl(C₁₋₆ alkyl).

Embodiment 22

The compound of embodiment 21, wherein the substituted or unsubstitutedheterocycloalkyl(C₁₋₆ alkyl) is a substituted or unsubstitutedgalactosyl.

Embodiment 23

The compound of embodiment 1, wherein B_(Nuc(a)) is a naturallyoccurring purine.

Embodiment 24

The compound of embodiment 1, wherein B_(Nuc(a)) is a naturallyoccurring pyrimidine.

Embodiment 25

The compound of embodiment 1, wherein B_(Nuc(a)) is a non-naturallyoccurring purine.

Embodiment 26

The compound of embodiment 1, wherein B_(Nuc(a)) is a non-naturallyoccurring pyrimidine.

Embodiment 27

The compound of embodiment 1, wherein B_(Nuc(a)) is selected from thegroup consisting of:

Embodiment 28

The compound of embodiment 1, wherein the compound has the structure:

Embodiment 29

The compound of embodiment 1, wherein the compound has the structure:

Embodiment 30

The compound of embodiment 1, wherein the compound has the

Embodiment 31

The compound of embodiment 1, wherein the compound is selected from anyone of the compounds in Tables 1-10, or a pharmaceutically acceptablesalt, hydrate, solvate or crystalline form thereof.

Embodiment 32

The compound of embodiment 1, wherein the compound is selected from thegroup consisting of:

or a pharmaceutically acceptable salt, hydrate, solvate or crystallineform of any of the foregoing.

Embodiment 33

A pharmaceutical composition including an effective amount of a compoundof any one of embodiments 1-32, or a pharmaceutically acceptable salt,hydrate, solvate or crystalline form thereof, and a pharmaceuticallyacceptable excipient.

Embodiment 34

The pharmaceutical composition of embodiment 33, wherein thepharmaceutical composition is in the form of a cream, a gel or anointment.

Embodiment 35

The pharmaceutical composition of embodiment 33 or 34, wherein thepharmaceutical composition is a topical formulation.

Embodiment 36

Use of a compound of any one of embodiments 1-32, or a pharmaceuticallyacceptable salt, hydrate, solvate or crystalline form thereof, in thepreparation of a medicament for treating a viral disease in a subject,wherein the viral disease is selected from the group consisting of humanpapilloma virus, HIV, hepatitis B virus, hepatitis C virus, variolavirus, vaccinia virus, an adenovirus, a cytomegalovirus, herpes simplexvirus 1, herpes simplex virus 2, Epstein Barr virus, BK virus, JC virus,feline leukemia virus and feline immunodeficiency virus.

Embodiment 37

The use of embodiment 36, wherein said virus is human papilloma virus.

Embodiment 38

The use of embodiment 37, said compound, or a pharmaceuticallyacceptable salt, hydrate, solvate or crystalline form thereof, for usein treating a plurality of types of human papilloma virus.

Embodiment 39

The use of embodiment 37, wherein the human papilloma virus is selectedfrom the group consisting human papilloma virus type 11, type 16 andtype 18.

Embodiment 40

Use of a compound of any one of embodiments 1-32, or a pharmaceuticallyacceptable salt, hydrate, solvate or crystalline form thereof, in thepreparation of a medicament for treating cancer of the cervix in asubject.

Embodiment 41

Use of a compound of any one of embodiments 1-32, or a pharmaceuticallyacceptable salt, hydrate, solvate or crystalline form thereof, in thepreparation of a medicament for inhibiting growth of a cell transformedby a virus, wherein the virus is selected from the group consisting ofhuman papilloma virus, HIV, hepatitis B virus, hepatitis C virus,variola virus, vaccinia virus, an adenovirus, a cytomegalovirus, herpessimplex virus 1, herpes simplex virus 2, Epstein Barr virus, BK virus,JC virus, feline leukemia virus and feline immunodeficiency virus.

Embodiment 42

A compound of any one of embodiments 1-32, or a pharmaceuticallyacceptable salt, hydrate, solvate or crystalline form thereof, for usein treating a viral disease in a subject, wherein the viral disease isselected from the group consisting of human papilloma virus, HIV,hepatitis B virus, hepatitis C virus, variola virus, vaccinia virus, anadenovirus, a cytomegalovirus, herpes simplex virus 1, herpes simplexvirus 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virusand feline immunodeficiency virus.

Embodiment 43

The compound of embodiment 42, wherein said virus is human papillomavirus.

Embodiment 44

The compound of embodiment 43, or a pharmaceutically acceptable salt,hydrate, solvate or crystalline form thereof, for use in treating aplurality of types of human papilloma virus.

Embodiment 45

The compound of embodiment 43, wherein the human papilloma virus isselected from the group consisting human papilloma virus type 11, type16 and type 18.

Embodiment 46

A compound of any one of embodiments 1-32, or a pharmaceuticallyacceptable salt, hydrate, solvate or crystalline form thereof, for usein treating cancer of the cervix in a subject.

Embodiment 47

A compound of any one of embodiments 1-32, or a pharmaceuticallyacceptable salt, hydrate, solvate or crystalline form thereof, for usein inhibiting growth of a cell transformed by a virus, wherein the virusis selected from the group consisting of human papilloma virus, HIV,hepatitis B virus, hepatitis C virus, variola virus, vaccinia virus, anadenovirus, a cytomegalovirus, herpes simplex virus 1, herpes simplexvirus 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virusand feline immunodeficiency virus.

Embodiment 48

A method for synthesis of the compound of Formula (Ia) according toEmbodiment 1:

wherein: B_(Nuc(a)) is a naturally occurring purine, a naturallyoccurring pyrimidine, a non-naturally occurring purine or anon-naturally occurring pyrimidine; L^(a) is an unsubstituted C₁₂₋₂₄alkyl, an unsubstituted C₁₃₋₂₉ heteroalkyl or a substituted glycerylmoiety, wherein the glyceryl moiety is substituted with one or moregroups selected from an unsubstituted C₁₃₋₂₉ alkyl, an unsubstitutedC₁₃₋₂₉ heteroalkyl, a substituted or unsubstituted aryl(C₁₋₆ alkyl), asubstituted or unsubstituted heteroaryl(C₁₋₆ alkyl) and a substituted orunsubstituted heterocycloalkyl(C₁₋₆ alkyl); R^(a) is selected from thegroup consisting of an unsubstituted C₁₋₆ alkyl, a substituted orunsubstituted aryl, a substituted or unsubstituted heteroaryl, asubstituted or unsubstituted heterocycloalkyl, a substituted orunsubstituted aryl(C₁₋₆ alkyl), a substituted or unsubstitutedheteroaryl(C₁₋₆ alkyl) and a substituted or unsubstitutedheterocycloalkyl(C₁₋₆ alkyl); X^(a) is hydrogen, an unsubstituted C₁₋₆alkyl, a halogen substituted C₁₋₆ alkyl, a hydroxy substituted C₁₋₆alkyl or an unsubstituted C₁₋₆ alkoxy; and Y^(a) is a leaving group; themethod including: contacting a compound of Formula (2-1a) that has aprotected B_(Nuc(a)) with a compound of Formula (2-2a) in the presenceof a strong base to form a compound of Formula (2-3a); and reacting thecompound of Formula (2-3a) with L^(a)-OH in the presence of a couplingagent to form the compound of Formula (Ia).

What is claimed is:
 1. A compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof:

wherein: B_(Nuc(a)) is a naturally occurring purine, a naturallyoccurring pyrimidine, or 2,6-diaminopurine; L^(a) is a substitutedglyceryl moiety having the formula —CH₂CH(OR¹)—CH₂(OR²), wherein R¹ andR² are independently selected from an unsubstituted C₁₃₋₂₉ alkyl, anunsubstituted C₁₃₋₂₉ heteroalkyl, a substituted or unsubstitutedaryl-C₁₋₆ alkyl, a substituted or unsubstituted heteroaryl-C₁₋₆ alky anda substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl; R^(a) isselected from the group consisting of a substituted or unsubstitutedaryl, a substituted or unsubstituted heteroaryl, a substituted orunsubstituted heterocycloalkyl, a substituted or unsubstituted aryl-C₁₋₆alkyl, a substituted or unsubstituted heteroaryl-C₁₋₆ alkyl and asubstituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl; X^(a) ishydrogen, an unsubstituted C₁₋₆ alkyl, a halogen substituted C₁₋₆ alkyl,a hydroxy substituted C₁₋₆ alkyl or an unsubstituted C₁₋₆ alkoxy; andwherein the substituent is selected from —OH, —NH₂, —SH, —CN, —CF₃,—NO₂, oxo, halogen, unsubstituted alkyl, unsubstituted heteroalkyl,unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstitutedaryl, and unsubstituted heteroaryl.
 2. The compound of claim 1, whereinX^(a) is hydrogen.
 3. The compound of claim 1, wherein X^(a) is methyl.4. The compound of claim 1, wherein X^(a) is methoxy.
 5. The compound ofclaim 1, wherein X^(a) is a fluoro substituted C₁₋₆ alkyl.
 6. Thecompound of claim 5, wherein X^(a) is a CH₂F.
 7. The compound of claim1, wherein X^(a) is a CH₂OH.
 8. The compound of claim 1, wherein L^(a)is a substituted glyceryl moiety, wherein the glyceryl moiety issubstituted with an unsubstituted C₁₃₋₂₉ alkyl.
 9. The compound of claim8, wherein L^(a) has the structure—(CH₂)—CH(OR^(a1))—(CH₂)—O(CH₂)₁₁₋₂₁—CH₃, wherein R^(a1) is asubstituted or unsubstituted aryl-C₁₋₆ alkyl, a substituted orunsubstituted heteroaryl-C₁₋₆ alkyl or a substituted or unsubstitutedheterocycloalkyl-C₁₋₆ alkyl.
 10. The compound of claim 9, wherein L^(a)has the structure


11. The compound of claim 1, wherein R^(a) is a substituted orunsubstituted aryl.
 12. The compound of claim 11, wherein thesubstituted or unsubstituted aryl is a substituted or unsubstitutedphenyl.
 13. The compound of claim 11 wherein the substituted orunsubstituted aryl is a substituted or unsubstituted naphthyl.
 14. Thecompound of claim 1, wherein R^(a) is a substituted or unsubstitutedaryl-C₁₋₆ alkyl.
 15. The compound of claim 14, wherein the substitutedor unsubstituted aryl-C₁₋₆ alkyl is a substituted or unsubstitutedbenzyl.
 16. The compound of claim 1, wherein R^(a) is a substituted orunsubstituted heterocycloalkyl-C₁₋₆ alkyl.
 17. The compound of claim 16,wherein the substituted or unsubstituted heterocycloalkyl-C₁₋₆ alkyl isa substituted or unsubstituted galactosyl.
 18. The compound of claim 1,wherein B_(Nuc(a)) is a naturally occurring purine.
 19. The compound ofclaim 1, wherein B_(Nuc(a)) is a naturally occurring pyrimidine.
 20. Thecompound of claim 1, wherein B_(Nuc(a)) is 2,6-diaminopurine.
 21. Thecompound of claim 1, wherein B_(Nuc(a)) is guanine, adenine, cytosine,thymine, or uracil.
 22. The compound of claim 1, wherein B_(Nuc(a)) isselected from the group consisting of:


23. The compound of claim 1, wherein the compound has the structure:


24. The compound of claim 1, wherein the compound has the structure:


25. The compound of claim 1, wherein the compound has the structure:

wherein X^(a) is an unsubstituted C₁₋₆ alkyl, a halogen substituted C₁₋₆alkyl, a hydroxy substituted C₁₋₆ alkyl or an unsubstituted C₁₋₆ alkoxy.26. The compound of claim 1, wherein the compound is selected from thegroup consisting of:

or a pharmaceutically acceptable salt of any of the foregoing.
 27. Thecompound of claim 1, wherein the compound is

or a pharmaceutically acceptable salt.
 28. The compound of claim 1,wherein the compound is

or a pharmaceutically acceptable salt.
 29. A pharmaceutical compositioncomprising an effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 30. The pharmaceutical composition of claim 29,wherein the pharmaceutical composition is a topical formulation.
 31. Thepharmaceutical composition of claim 30, wherein the pharmaceuticalcomposition is in the form of a cream, a gel or an ointment.
 32. Amethod for treating human papilloma virus in a subject in need thereof,comprising administering a compound of claim 1, optionally in apharmaceutically acceptable carrier.
 33. The method of claim 32, whereinthe human papilloma virus is type 52 or
 58. 34. The method of claim 32,wherein the human papilloma virus is type 11, type 16 or type
 18. 35. Amethod for treating cancer of the cervix in a subject in need thereof,comprising administering a compound of claim 1, optionally in apharmaceutically acceptable carrier.
 36. A method for treating cervicalintraepithelial neoplasia (CIN), anal intraepithelial neoplasia (AIN),and vulvar intraepithelial neoplasia (VIN) in a subject in need thereof,comprising administering a compound of claim 1, optionally in apharmaceutically acceptable carrier.